The DOI matches its Crossref record; 268 of the 278 references it cites were found in a registry or an index; 3 of the 298 sources its claims cite were checked for support.
Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications
Open accessAbstract
The prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level cognitive and emotional processes. Its local circuits among glutamatergic principal neurons and GABAergic interneurons, as well as its long-range connections with other brain regions, have been functionally linked to specific behaviors, ranging from working memory to reward seeking. The efficacy of synaptic signaling in the PFC network is profundedly influenced by monoaminergic inputs via the activation of dopamine, adrenergic, or serotonin receptors. Stress hormones and neuropeptides also exert complex effects on the synaptic structure and function of PFC neurons. Dysregulation of PFC synaptic transmission is strongly linked to social deficits, affective disturbance, and memory loss in brain disorders, including autism, schizophrenia, depression, and Alzheimer's disease. Critical neural circuits, biological pathways, and molecular players that go awry in these mental illnesses have been revealed by integrated electrophysiological, optogenetic, biochemical, and transcriptomic studies of PFC. Novel epigenetic mechanism-based strategies are proposed as potential avenues of therapeutic intervention for PFC-involved diseases. This review provides an overview of PFC network organization and synaptic modulation, as well as the mechanisms linking PFC dysfunction to the pathophysiology of neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Insights from the preclinical studies offer the potential for discovering new medical treatments for human patients with these brain disorders.
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238 Not checked yet · 17 Own interpretation · 2 Supported · 1 Partly supported · accuracy not yet measured
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In the paper
“D2R overexpression in mouse striatum causes the reduced inhibitory synaptic input to PFC pyramidal neurons, suggesting that the deficit in PFC GABAergic function in schizophrenia could be secondary to alterations in the striatal dopamine system 188.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Supportedcites [188] Li YC, Kellendonk C, Simpson EH, Kandel ER, Gao WJ. D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:12107–12. source
The Discussion (passage 1; page not supplied) explicitly raises the possibility that decreased PFC GABAergic function in schizophrenia could be secondary to alterations in the striatal dopamine system. It grounds that suggestion in reduced inhibitory transmission observed in the D2R-overexpressing mouse model, matching the citing sentence's tentative wording. (LLM, conf=0.94)
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In the paper
“The key findings is that in a delayed reaching task, some primate dorsolateral PFC neurons exhibit the increased firing during the delay period when response-related information needs to be held in mind to guide the subsequent execution of correct responses 4,5.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
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In the paper
“Electro-physiological and pharmacological evidence further supports the existence of a frontal cortical area in the rat that exhibits increased firing during the delay period in the absence of sensory stimulus that instruct the orienting response, as in primate PFC 13.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [13] Erlich JC, Bialek M, Brody CD. A cortical substrate for memory-guided orienting in the rat. Neuron. 2011;72:330–43. source
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In the paper
“A spatiotemporal dynamic network, which originates in PFC and ventral striatum, relays through the amygdala and ventral tegmental area (VTA), and converges in ventral hippocampus (vHIP), is found to encode depression vulnerability in mice subjected to social defeat stress 20.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [20] Hultman R, Ulrich K, Sachs BD, Blount C, Carlson DE, Ndubuizu N, et al. Brain-wide electrical spatiotemporal dynamics encode depression vulnerability. Cell. 2018;173:166–80.e114. source
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In the paper
“Dorsomedial PFC exerts the top-down control of motor cortex ensembles to inhibit inappropriate responses during a delayed-response task 18.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [18] Narayanan NS, Laubach M. Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex. Neuron. 2006;52:921–31. source
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In the paper
“The reciprocal connection between PFC and BLA is implicated in reward-seeking and fear-related responses, and optogenetic studies have revealed that BLA to PL circuit is critical in governing the selection of behavioral responses amid conflicting cues of reward and punishment 26.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [26] Burgos-Robles A, Kimchi EY, Izadmehr EM, Porzenheim MJ, Ramos-Guasp WA, Nieh EH, et al. Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment. Nat Neurosci. 2017;20:824–35. source
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In the paper
“Proper vHIP-mPFC signaling is necessary to recall social memories 22.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [22] Phillips ML, Robinson HA, Pozzo-Miller L. Ventral hippocampal projections to the medial prefrontal cortex regulate social memory. eLife. 2019;8:e44182. source
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In the paper
“The delayed and persistent spiking activity that encodes spatial “working memory” signals arises from recurrent excitation among PFC pyramidal neurons 5,6.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [5] Goldman-Rakic PS. Cellular basis of working memory. Neuron. 1995;14:477–85. source
- Not checked yetcites [6] Wang Y, Markram H, Goodman PH, Berger TK, Ma J, Goldman-Rakic PS. Heterogeneity in the pyramidal network of the medial prefrontal cortex. Nat Neurosci. 2006;9:534–42. source
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In the paper
“Cortical network models predict that NMDA receptors subserve the recurrent synaptic excitation and persist firing of PFC pyramidal neurons during working memory 7,8.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [7] Compte A, Brunel N, Goldman-Rakic PS, Wang XJ. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Cereb Cortex. 2000;10:910–23. source
- Not checked yetcites [8] Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, et al. NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron. 2013;77:736–49. source
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In the paper
“PFC in awake mice also has a basic disinhibitory circuit module in which activation of VIP+ interneurons transiently suppresses primarily SST+ and a fraction of PV+ interneurons 30.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [30] Pi HJ, Hangya B, Kvitsiani D, Sanders JI, Huang ZJ, Kepecs A. Cortical interneurons that specialize in disinhibitory control. Nature. 2013;503:521–4. source
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In the paper
“Recordings of neuronal ensembles in rats during new task learning further find that the dynamic changes in PFC neuronal activity parallel with behavioral decoding, suggesting that working memory can be mediated by dynamic activation of different neural populations in PFC 14.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [14] Baeg EH, Kim YB, Huh K, Mook-Jung I, Kim HT, Jung MW. Dynamics of population code for working memory in the prefrontal cortex. Neuron. 2003;40:177–88. source
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In the paper
“Early studies of macaque monkeys have revealed PFC as a crucial hub necessary for successful maintenance of working memory (WM), a cognitive process involving information holding and manipulation, which serves as the fundamental backbone for executive functions 2,3.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
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In the paper
“A specific subset of mPFC projections to NAc neurons encodes the decision to initiate or suppress reward seeking when faced with risk of punishment 17.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [17] Kim CK, Ye L, Jennings JH, Pichamoorthy N, Tang DD, Yoo AW, et al. Molecular and circuit-dynamical identification of top-down neural mechanisms for restraint of reward seeking. Cell. 2017;170:1013–27.e1014. source
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In the paper
“PV+ interneurons in mPFC also play a key role in social behaviors: activation of mPFC PV+ neurons rescues social memory impairment caused by vHIP inhibition 33.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [33] Sun Q, Li X, Li A, Zhang J, Ding Z, Gong H, et al. Ventral hippocampal-prefrontal interaction affects social behavior via parvalbumin positive neurons in the medial prefrontal cortex. iScience. 2020;23:100894. source
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In the paper
“The relapse of extinguished fear is found to be mediated by a feedforward inhibitory pathway from ventral hippocampus to IL cortex, which involves the recruitment of PV+ interneurons in IL 43.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [43] Marek R, Jin J, Goode TD, Giustino TF, Wang Q, Acca GM, et al. Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nat Neurosci. 2018;21:384–92. source
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In the paper
“These results have unmasked a role of dopamine in regulating the temporal dynamics of excitation/inhibition balance in VTA-PFC circuit.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
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In the paper
“monoaminergic modulation of the efficacy of synaptic connections in PFC circuits has profound effects on PFC-mediated executive function, including working memory, regulation of attention, inhibition of inappropriate behaviors, and impulsivity control 45.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Regulation of PFC Synaptic Function > Monoaminergic regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [45] Robbins TW, Arnsten AF. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci. 2009;32:267–87. source
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In the paper
“D4 receptors suppress AMPARs in PFC GABAergic interneurons via the unique calcineurin/Slingshot/cofilin signaling mechanism 64.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [64] Yuen EY, Yan Z. Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex. J Neurosci. 2009;29:550–62. source
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In the paper
“Stimulation of D1R produces an inverted-U dose response on PFC neuronal firing and cognitive performance during working memory tasks 46.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [46] Arnsten AF. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011;69:e89–99. source
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In the paper
“In the avoidance behavior of elevated plus maze, PFC VIP+ interneurons enable cortical circuits to integrate hippocampal inputs, therefore effectively gating the transmission of signals related to open arm avoidance across hippocampal-prefrontal network 44”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [44] Lee AT, Cunniff MM, See JZ, Wilke SA, Luongo FJ, Ellwood IT, et al. VIP interneurons contribute to avoidance behavior by regulating information flow across hippocampal-prefrontal networks. Neuron. 2019;102:1223–34.e1224. source
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In the paper
“Moreover, in a social fear conditioning paradigm, SST+ interneurons suppress PV+ interneurons and disinhibit pyramidal cells, which consequently enhances PFC output to mediate social fear responses 42.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [42] Xu H, Liu L, Tian Y, Wang J, Li J, Zheng J, et al. A disinhibitory microcircuit mediates conditioned social fear in the prefrontal cortex. Neuron. 2019;102:668–5. source
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In the paper
“genetic studies have linked novelty-seeking behavior and ADHD to long-repeat D4R allele (hD4.7) 57,67.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [57] LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, et al. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996;1:121–4.
- Not checked yetcites [67] Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, et al. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet. 1996;12:78–80. source
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In the paper
“Stress exposure in D4R knockout mice induces schizophrenia-like behaviors via disruption of GABAergic transmission in PFC 66.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [66] Tan T, Wang W, Williams J, Ma K, Cao Q, Yan Z. Stress exposure in dopamine D4 receptor knockout mice induces schizophrenia-like behaviors via disruption of GABAergic transmission. Schizophr Bull. 2019;45:1012–23. source
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In the paper
“Activation of NAc-projecting PL neurons, but not the other subpopulations, decreases the preference for a social target 32.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [32] Murugan M, Jang HJ, Park M, Miller EM, Cox J, Taliaferro JP, et al. Combined social and spatial coding in a descending projection from the prefrontal cortex. Cell. 2017;171:1663–77.e1616. source
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In the paper
“It has been revealed that D4 receptors serve as a homeostatic synaptic factor to stabilize cortical excitability by dynamically regulating CaMKII 58,59 and the downstream NMDA and AMPA receptor channels 60–62.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [58] Gu Z, Jiang Q, Yuen EY, Yan Z. Activation of dopamine D4 receptors induces synaptic translocation of Ca2+/calmodulin-dependent protein kinase II in cultured prefrontal cortical neurons. Mol Pharmacol. 2006;69:813–22. source
- Not checked yetcites [59] Gu Z, Yan Z. Bidirectional regulation of Ca2+/calmodulin-dependent protein kinase II activity by dopamine D4 receptors in prefrontal cortex. Mol Pharmacol. 2004;66:948–55. source
- Not checked yetcites [60] Wang X, Zhong P, Gu Z, Yan Z. Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex. J Neurosci. 2003;23:9852–61. source
- Not checked yetcites [61] Wang X, Gu Z, Zhong P, Chen G, Feng J, Yan Z. Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure. Mol Cell Neurosci. 2006;31:15–25. source
- Not checked yetcites [62] Yuen EY, Zhong P, Yan Z. Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors. Proc Natl Acad Sci USA. 2010;107:22308–13. source
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In the paper
“BLA inputs also make strong connections onto PFC PV+ and SST+ interneurons, driving feedforward inhibition of PFC pyramidal neurons 35,36.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [35] McGarry LM, Carter AG. Inhibitory gating of basolateral amygdala inputs to the prefrontal cortex. J Neurosci. 2016;36:9391–406. source
- Not checked yetcites [36] Dilgen J, Tejeda HA, O’Donnell P. Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex. J Neurophysiol. 2013;110:221–9. source
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In the paper
“A subclass of VIP neurons expressing ChAT, ChAT-VIP, directly excites neurons throughout cortical layers via fast synaptic transmission of acetylcholine in mPFC, providing a local source to control attention 31.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [31] Obermayer J, Luchicchi A, Heistek TS, de Kloet SF, Terra H, Bruinsma B, et al. Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention. Nat Commun. 2019;10:5280. source
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In the paper
“Dopamine also reduces recurrent excitation in layer V pyramidal neurons 50”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [50] Gao WJ, Krimer LS, Goldman-Rakic PS. Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proc Natl Acad Sci USA. 2001;98:295–300. source
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In the paper
“Moreover, the effects of α1-ARs and α2-ARs are differentially modified by RGS4 73”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Noradrenaline
What the sources say
- Not checked yetcites [73] Liu W, Yuen EY, Allen PB, Feng J, Greengard P, Yan Z. Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Proc Natl Acad Sci USA. 2006;103:18338–43. source
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In the paper
“This stress-induced loss of glutamate receptor expression is attributable to the increased ubiquitin/proteasome-mediated degradation of GluR1 and NR1 that is controlled by E3 ubiquitin ligases Nedd4 and Fbx2”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [110] Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77. source
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In the paper
“Transcriptomic analysis of autistic brains has found 444 genes showing significant expression changes in PFC, but only 2 in cerebellum 123.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [123] Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474:380–4. source
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In the paper
“Serotonergic regulation of GABA transmission in PFC is subject to the alteration by corticotropin-releasing factor (CRF) in response to stressful stimuli 89 or chronic antidepressant treatment 86.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin
What the sources say
- Not checked yetcites [89] Tan H, Zhong P, Yan Z. Corticotropin-releasing factor and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. J Neurosci. 2004;24:5000–8. source
- Not checked yetcites [86] Zhong P, Yan Z. Chronic antidepressant treatment alters serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. Neuroscience. 2004;129:65–73. source
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In the paper
“Synaptic plasticity deficits in PFC of animal models have been linked to clinical findings from human patients with frontal cortical dysfunction, including the decreased functional connectivity in prefrontal-limbic circuits, executive function and memory deficits, inflexible and maladaptive behaviors 121.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Dysregulation and Diseases
What the sources say
- Not checked yetcites [121] Price RB, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry. 2020;25:530–43. source
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In the paper
“In the human PFC, serotonin suppresses monosynaptic excitatory connections from pyramidal cells to interneurons 90.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin
What the sources say
- Not checked yetcites [90] Komlósi G, Molnár G, Rózsa M, Oláh S, Barzó P, Tamás G. Fluoxetine (prozac) and serotonin act on excitatory synaptic transmission to suppress single layer 2/3 pyramidal neuron-triggered cell assemblies in the human prefrontal cortex. J Neurosci. 2012;32:16369–78. source
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In the paper
“Acute stress, via acting on GR, also induces a delayed potentiation of NMDAR-and AMPAR-mediated synaptic currents, which is correlated with the increased level of synaptic NMDAR and AMPAR subunits 96,98.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [96] Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z. Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci USA. 2009;106:14075–9. source
- Not checked yetcites [98] Yuen EY, Liu W, Karatsoreos IN, Ren Y, Feng J, McEwen BS, et al. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry. 2011;16:156–70. source
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In the paper
“serotonin also affects GABAergic fast-spiking interneurons in PFC by enhancing their excitability and gamma frequency temporal integration via 5-HT2A suppression of an inward-rectifying potassium conductance 92.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin
What the sources say
- Not checked yetcites [92] Athilingam JC, Ben-Shalom R, Keeshen CM, Sohal VS, Bender KJ. Serotonin enhances excitability and gamma frequency temporal integration in mouse prefrontal fast-spiking interneurons. eLife. 2017;6:e31991. source
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In the paper
“REDD1 knockdown renders animals to have greater resilience to the chronic stress-induced spine shrinkage and AMPAR current reduction 114.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [114] Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat Med. 2014;20:531–5. source
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In the paper
“Postmortem studies have found focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from a majority of young children with autism, with the clearest signs of abnormal expression of excitatory neuronal markers in deep cortical layers 4 and 5 122.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [122] Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, et al. Patches of disorganization in the neocortex of children with autism. N. Engl J Med. 2014;370:1209–19. source
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In the paper
“The transcription of Nedd4 is upregulated by repeated stress via an epigenetic mechanism involving the elevated histone deacetylase 2 (HDAC2) and the ensuing suppression of histone methyltransferase Ehmt2 (also known as G9a) that catalyzes the repressive mark H3K9me2 111.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [111] Wei J, Xiong Z, Lee JB, Cheng J, Duffney LJ, Matas E, et al. Histone modification of Nedd4 ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress. J Neurosci. 2016;36:2119–30. source
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In the paper
“Serum-and glucocorticoid-inducible kinases (SGKs), an immediate early gene activated by stress hormone, is shown to be involved by enhancing Rab4-mediated trafficking of glutamate receptors from early endosomes to plasma membrane in PFC neurons 98,99.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [98] Yuen EY, Liu W, Karatsoreos IN, Ren Y, Feng J, McEwen BS, et al. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry. 2011;16:156–70. source
- Not checked yetcites [99] Liu W, Yuen EY, Yan Z. The stress hormone corticosterone increases synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors via serum- and glucocorticoid-inducible kinase (SGK) regulation of the GDI-Rab4 complex. J Biol Chem. 2010;285:6101–8. source
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In the paper
“Exposing animals to an acute stressor, such as forced swim, foot shock or restraint, produces significantly enhanced glutamatergic transmission in PFC circuitry 94–97.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [94] Wang M, Perova Z, Arenkiel BR, Li B. Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress. J Neurosci. 2014;34:7485–92. source
- Not checked yetcites [95] Treccani G, Musazzi L, Perego C, Milanese M, Nava N, Bonifacino T, et al. Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex. Mol Psychiatry. 2014;19:433–43. source
- Not checked yetcites [96] Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z. Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci USA. 2009;106:14075–9. source
- Not checked yetcites [97] Lee JB, Wei J, Liu W, Cheng J, Feng J, Yan Z. Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex. J Physiol. 2012;590:1535–46. source
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In the paper
“A prominent loss of GluR1 and NR1 subunit expression has been found in PFC pyramidal neurons from repeatedly stressed animals, which leads to the depression of AMPAR- and NMDAR-mediated synaptic currents 110.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [110] Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77. source
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In the paper
“Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at postsynaptic density of glutamatergic synapses, has been causally linked to autism 124,125.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [124] Bonaglia MC, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A, et al. Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet. 2001;69:261–8. source
- Not checked yetcites [125] Betancur C, Buxbaum JD. SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism. 2013;4:17. source
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In the paper
“Large scale genetic screenings have revealed that many of the identified top-ranking autism risk factors are genes implicated in synaptic homeostasis, transcriptional regulation and chromatin remodeling pathways 140–142.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [140] Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell. 2020;180:568–.e523. source
- Not checked yetcites [141] De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15. source
- Not checked yetcites [142] Coe BP, Stessman HAF, Sulovari A, Geisheker MR, Bakken TE, Lake AM, et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat Genet. 2019;51:106–16. source
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In the paper
“One of the misregulated proteins resulting from forebrain Cul3-deficiency is Smyd3, a histone methyltransferase involved in gene transcription.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [147] Rapanelli M, Tan T, Wang W, Wang X, Wang ZJ, Zhong P, et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry 2019. source
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In the paper
“These studies have demonstrated how aberrations in molecular and epigenetic pathways implicated in autism are interconnected.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
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In the paper
“A histone acetylome-wide association study (H3K27ac ChIP-seq) of human ASD postmortem samples also reveals common “epimutations” on genes involved in synaptic transmission, ion transport, and histone deacetylation 148.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [148] Sun W, Poschmann J, Cruz-Herrera Del Rosario R, Parikshak NN, Hajan HS, Kumar V, et al. Histone acetylome-wide association study of autism spectrum disorder. Cell. 2016;167:1385–1397.e1311. source
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In the paper
“Epigenomic studies show that PFC neurons from subjects with autism exhibit the altered H3K4me3 peaks at numerous genes regulating neuronal connectivity, social behaviors, and cognition, often in conjunction with altered expression of the corresponding transcripts 143.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [143] Shulha HP, Cheung I, Whittle C, Wang J, Virgil D, Lin CL, et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry. 2012;69:314–24. source
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In the paper
“Moreover, the repressive histone mark H3K9me2 and its catalyzing enzymes EHMT1/2 are selectively increased in the PFC of Shank3-deficient mice and autistic human postmortem brains 146.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [146] Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, et al. Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry. 2019;25:2517–33. source
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In the paper
“suggesting that targeting actin regulators to restore actin-based NMDAR synaptic delivery could be a therapeutic option for autism 128.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [128] Yan Z, Kim E, Datta D, Lewis DA, Soderling SH. Synaptic actin dysregulation, a convergent mechanism of mental disorders? J Neurosci. 2016;36:11411–7. source
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In the paper
“SZ patients exhibit reduced gray matter in frontal cortex, evidenced by MRI studies 152,153.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [152] Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A, et al. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiatry. 2000;57:471–80. source
- Not checked yetcites [153] Goldstein JM, Goodman JM, Seidman LJ, Kennedy DN, Makris N, Lee H, et al. Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. Arch Gen Psychiatry. 1999;56:537–47. source
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In the paper
“Another identified high-risk factor for autism is the Cullin 3 (Cul3) gene 141”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [141] De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15. source
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In the paper
“Another prominent genetic link to autism spectrum disorders and intellectual disability is the microdeletion or microduplication of the human 16p11.2 gene locus 131,132.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [131] Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl J Med. 2008;358:667–75. source
- Not checked yetcites [132] Rein B, Yan Z. 16p11.2 copy number variations and neurodevelopmental disorders. Trends Neurosci. 2020;43:886–901. source
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In the paper
“A 16p11.2 deletion mouse model, 16p11+/−, exhibits NMDAR hypofunction in PFC pyramidal neurons 133.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [133] Wang W, Rein B, Zhang F, Tan T, Zhong P, Qin L, et al. Chemogenetic activation of prefrontal cortex rescues synaptic and behavioral deficits in a mouse model of 16p11.2 deletion syndrome. J Neurosci. 2018;38:5939–48. source
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In the paper
“A recent series of studies have shown that targeting epigenetic enzymes to adjust gene expression and ameliorate synaptic defects in PFC is a potential strategy to normalize behavioral phenotypes associated with autism 144–147.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [144] Ma K, Qin L, Matas E, Duffney LJ, Liu A, Yan Z. Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism. Neuropsychopharmacology. 2018;43:1779–88. source
- Not checked yetcites [145] Qin L, Ma K, Wang ZJ, Hu Z, Matas E, Wei J, et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci. 2018;21:564–75. source
- Not checked yetcites [146] Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, et al. Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry. 2019;25:2517–33. source
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In the paper
“The nucleocytoplasmic shuttle protein involved in both cell adhesion and transcriptional regulation, β-catenin, is found to link the loss of Shank3 in the synapse to the upregulation of HDAC2 and EHMT1/2 transcription in the nucleus 145,146 (Fig. 3).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [145] Qin L, Ma K, Wang ZJ, Hu Z, Matas E, Wei J, et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci. 2018;21:564–75. source
- Not checked yetcites [146] Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, et al. Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry. 2019;25:2517–33. source
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In the paper
“Synaptic dysfunction and excitation/inhibition imbalance is identified as a common pathophysiological feature of multiple ASD models 137–139.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [137] Lee E, Lee J, Kim E. Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry. 2017;81:838–47. source
- Not checked yetcites [138] Spratt PWE, Ben-Shalom R, Keeshen CM, Burke KJ Jr, Clarkson RL, Sanders SJ, et al. The autism-associated gene Scn2a contributes to dendritic excitability and synaptic function in the prefrontal cortex. Neuron. 2019;103:673–.e675. source
- Not checked yetcites [139] Lazaro MT, Taxidis J, Shuman T, Bachmutsky I, Ikrar T, Santos R, et al. Reduced prefrontal synaptic connectivity and disturbed oscillatory population dynamics in the CNTNAP2 model of autism. Cell Rep. 2019;27:2567–.e2566. source
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In the paper
“In PFC pyramidal neurons of Shank3-deficient mice, NMDAR function and synaptic distribution are significantly diminished, which is caused by a marked loss of actin filaments at glutamatergic synapses due to the altered Rac1/PAK/cofilin signaling 127.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [127] Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400–13. source
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In the paper
“High-resolution MRI has found that loss of Shank3 in mice results in the disrupted local and long-range prefrontal and frontostriatal functional connectivity, which is predictive of social communication deficits 126.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [126] Pagani M, Bertero A, Liska A, Galbusera A, Sabbioni M, Barsotti N, et al. Deletion of autism risk gene Shank3 disrupts prefrontal connectivity. J Neurosci. 2019;39:5299–310. source
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In the paper
“In accordance with these theories, SZ patients display significant reductions in dendritic spine density in PFC 157”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [157] Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107. source
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In the paper
“In agreement with this, monkeys performing a SZ-relevant cognitive task exhibit the reduced synchronous firing and disrupted connectivity in PFC neurons after the administration of an NMDAR antagonist 175.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [175] Zick JL, Blackman RK, Crowe DA, Amirikian B, DeNicola AL, Netoff TI, et al. Blocking NMDAR disrupts spike timing and decouples monkey prefrontal circuits: implications for activity-dependent disconnection in schizophrenia. Neuron. 2018;98:1243–55.e1245. source
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In the paper
“while other presynaptic markers appear unchanged 177,179.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [177] Fung SJ, Sivagnanasundaram S, Weickert CS. Lack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients. Biol Psychiatry. 2011;69:71–79. source
- Not checked yetcites [179] Halim ND, Weickert CS, McClintock BW, Hyde TM, Weinberger DR, Kleinman JE, et al. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol Psychiatry. 2003;8:797–810. source
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In the paper
“and the significantly lower postsynaptic expression of the NMDAR subunit NR1 and PSD95 178.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [178] Catts VS, Derminio DS, Hahn CG, Weickert CS. Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia. npj Schizophr. 2015;1:15037. source
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In the paper
“an expression analysis of DLPFC from SZ patients indicated the reduced expression of several GABA-related genes, including neuropeptides and both presynaptic and postsynaptic markers 183.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [183] Hashimoto T, Arion D, Unger T, Maldonado-Avilés JG, Morris HM, Volk DW, et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2008;13:147–61. source
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In the paper
“It has thus been postulated that the NMDA hypofunction in SZ mainly occurs in cortical GABAergic interneurons 165.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [165] Nakazawa K, Jeevakumar V, Nakao K. Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia. npj Schizophr. 2017;3:7. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“is thought to contribute to PFC dysfunction in SZ.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [186] Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004;74:1–58. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Several biochemical indicators of NMDA dysfunction are reported in SZ PFC, including the reduced expression of several synaptic plasticity-related genes 177”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [177] Fung SJ, Sivagnanasundaram S, Weickert CS. Lack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients. Biol Psychiatry. 2011;69:71–79. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“While no change in the number of PV+ cells 181”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [181] Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23:6315–26. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Inhibiting GABAergic transmission in PFC of rats produces several behavioral phenotypes mirroring SZ symptomology 184.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [184] Enomoto T, Tse MT, Floresco SB. Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia. Biol Psychiatry. 2011;69:432–41. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies suggest synaptic dysfunction in PFC as a core mechanism in SZ.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In rats treated with NMDAR antagonists, PFC neurons display the elevated and irregular spiking activity and the reduced coordinated burst firing, suggesting that NMDA hypofunction in PFC may drive disorganized network activity 174.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [174] Jackson ME, Homayoun H, Moghaddam B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci USA. 2004;101:8467–72. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“and/or are functionally implicated in synaptic transmission 162,163.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [162] Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013;154:518–29. source
- Not checked yetcites [163] Jaffe AE, Straub RE, Shin JH, Tao R, Gao Y, Collado-Torres L, et al. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat Neurosci. 2018;21:1117–25. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“PFC-specific inhibition of either NMDA or GABA transmission produces working memory deficits in rats, suggesting that either system could contribute to working memory deficits in SZ 176.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [176] Auger ML, Floresco SB. Prefrontal cortical GABAergic and NMDA glutamatergic regulation of delayed responding. Neuropharmacology. 2017;113:10–20. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The synaptic pathology of SZ in the PFC is complex, involving disrupted glutamatergic, GABAergic, dopaminergic, and serotonergic transmission (Fig. 4A).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“including the reduced density of NR2A-expressing PV interneurons in cortical layers 3 and 4 172”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [172] Bitanihirwe BK, Lim MP, Kelley JF, Kaneko T, Woo TU. Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia. BMC Psychiatry. 2009;9:71. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“form protein interactions in fetal dorsolateral (DL) and ventrolateral PFC 162”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [162] Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013;154:518–29. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“and lower density of perineuronal nets (PNN) - extracellular structures that stabilize synapses, also suggesting synaptic loss or destabilization 158.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [158] Mauney SA, Athanas KM, Pantazopoulos H, Shaskan N, Passeri E, Berretta S, et al. Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia. Biol Psychiatry. 2013;74:427–35. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“or the density of GABAergic synaptic inputs on DLPFC neurons 182 is observed in SZ patients”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [182] Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry. 2014;19:30–36. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced expression of the presynaptic vesicle protein VAMP has also been reported in SZ PFC 179”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [179] Halim ND, Weickert CS, McClintock BW, Hyde TM, Weinberger DR, Kleinman JE, et al. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol Psychiatry. 2003;8:797–810. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Dopamine modulation of PFC, which also plays a major role in working memory 186”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [186] Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004;74:1–58. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“and reduced functional connectivity between PFC and other brain regions when performing a cognitive task 160.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [160] Fornito A, Yücel M, Dean B, Wood SJ, Pantelis C. Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: bridging the gap between neuroimaging and neuropathology. Schizophr Bull. 2009;35:973–93. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“and the reduced density of GAD67- and NR2A-coexpressing neurons in layers 2 and 5 of anterior cingulate cortex 173.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [173] Woo TU, Walsh JP, Benes FM. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry. 2004;61:649–57. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“NMDAR antagonists may elicit this paradoxical response by primarily blocking NMDA receptors on GABAergic interneurons, thereby promoting disinhibition of pyramidal neurons 170.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [170] Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–11500. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“many high-risk SZ genes identified by GWAS studies are highly enriched in mid-frontal lobe 161”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [161] Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“PFC-specific inhibition of either NMDA or GABA transmission produces working memory deficits in rats, suggesting that either system could contribute to working memory deficits in SZ 176.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [176] Auger ML, Floresco SB. Prefrontal cortical GABAergic and NMDA glutamatergic regulation of delayed responding. Neuropharmacology. 2017;113:10–20. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“SZ patients show reduced blood flow in PFC during task performance 159”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [159] Goldman-Rakic PS, Selemon LD. Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull. 1997;23:437–58. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Paradoxically, MK-801 drives the increased release of glutamate in the mPFC, though the antipsychotic medications clozapine and haloperidol are both able to block MK-801-induced glutamate release in PFC of rats 169.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [169] López-Gil X, Babot Z, Amargós-Bosch M, Suñol C, Artigas F, Adell A. Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology. 2007;32:2087–97. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Paradoxically, MK-801 drives the increased release of glutamate in the mPFC, though the antipsychotic medications clozapine and haloperidol are both able to block MK-801-induced glutamate release in PFC of rats 169.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [169] López-Gil X, Babot Z, Amargós-Bosch M, Suñol C, Artigas F, Adell A. Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology. 2007;32:2087–97. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition to dopamine, serotonin dysfunction in PFC is also implicated in SZ, as 5-HT receptors are the major targets of many atypical antipsychotics used to treat SZ, such as clozapine and olanzapine.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“damage to VMPFC is associated with low levels of depression, and damage to DLPFC is associated with high levels of depression 206.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [206] Koenigs M, Huey ED, Calamia M, Raymont V, Tranel D, Grafman J. Distinct regions of prefrontal cortex mediate resistance and vulnerability to depression. J Neurosci. 2008;28:12341–8. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“D2R overexpression in mouse striatum causes the reduced inhibitory synaptic input to PFC pyramidal neurons, suggesting that the deficit in PFC GABAergic function in schizophrenia could be secondary to alterations in the striatal dopamine system 188.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [188] Li YC, Kellendonk C, Simpson EH, Kandel ER, Gao WJ. D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:12107–12. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Upregulation of HDAC1 is found in PFC of human SZ patients and Hdac1 overexpression in PFC is associated with SZ-like phenotypes in mice 202.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [202] Bahari-Javan S, Varbanov H, Halder R, Benito E, Kaurani L, Burkhardt S, et al. HDAC1 links early life stress to schizophrenia-like phenotypes. Proc Natl Acad Sci USA. 2017;114:E4686–E4694. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Protein expression levels of the NMDA subunits NR2A/NR2B and PSD95 are also reduced in PFC of MDD patients 210”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [210] Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33:70–75. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“ATAC-seq analysis of SZ DLPFC shows that genetic regions with high chromatin accessibility are highly enriched in heritable genetic risk factors for SZ 197.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [197] Bryois J, Garrett ME, Song L, Safi A, Giusti-Rodriguez P, Johnson GD, et al. Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun. 2018;9:3121. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Further postmortem studies have confirmed the reduced D1R expression in PFC of SZ patients 192.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [192] Kaalund SS, Newburn EN, Ye T, Tao R, Li C, Deep-Soboslay A, et al. Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. Mol Psychiatry. 2014;19:1258–66. source
boosted- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, the existing evidence suggests a model whereby the disruption of NMDA and GABA transmission in PFC, which is partially driven by aberrant dopamine and serotonin neuromodulation, produces excitation/inhibition imbalance and network dysconnectivity in SZ (Fig. 4A).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“damage to VMPFC is associated with low levels of depression, and damage to DLPFC is associated with high levels of depression 206.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [206] Koenigs M, Huey ED, Calamia M, Raymont V, Tranel D, Grafman J. Distinct regions of prefrontal cortex mediate resistance and vulnerability to depression. J Neurosci. 2008;28:12341–8. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“two histone markers associated with transcriptional activation (H3K4me3 and H3K27ac) are enriched at SZ genetic risk variants 198.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [198] Girdhar K, Hoffman GE, Jiang Y, Brown L, Kundakovic M, Hauberg ME, et al. Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci. 2018;21:1126–36. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“RNA-sequencing analyses of postmortem DLPFC from MDD patients similarly revealed the downregulation of genes related to glutamatergic transmission 211.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [211] Pantazatos SP, Huang YY, Rosoklija GB, Dwork AJ, Arango V, Mann JJ. Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity. Mol Psychiatry. 2017;22:760–73. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Epigenetic dysregulation of 5-HT2A receptor has been demonstrated in human frontal cortex 200.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [200] Abdolmaleky HM, Yaqubi S, Papageorgis P, Lambert AW, Ozturk S, Sivaraman V, et al. Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophr Res. 2011;129:183–90. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings suggest that epigenetic dysregulation of selective genes may play an important role in SZ.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“PET studies in SZ patients have similarly shown the reduced 5-HT2A availability in frontal cortex 194.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [194] Takano H. Cognitive function and monoamine neurotransmission in schizophrenia: evidence from positron emission tomography studies. Front Psychiatry. 2018;9:228. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Diminished expression of several synaptic genes, including CALM2, SYN1, RAB3A, RAB4B and TUBB4, is observed in PFC of MDD patients, along with reduced spine density in layers II/III of DLPFC 209.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [209] Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Upregulation of HDAC1 is found in PFC of human SZ patients and Hdac1 overexpression in PFC is associated with SZ-like phenotypes in mice 202.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [202] Bahari-Javan S, Varbanov H, Halder R, Benito E, Kaurani L, Burkhardt S, et al. HDAC1 links early life stress to schizophrenia-like phenotypes. Proc Natl Acad Sci USA. 2017;114:E4686–E4694. source
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In the paper
“The novel antipsychotic drug lurasidone restores the diminished NMDAR function in PFC pyramidal neurons from the phencyclidine (PCP) model of schizophrenia via antagonizing 5-HT7 receptors 195”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [195] Yuen EY, Li X, Wei J, Horiguchi M, Meltzer HY, Yan Z. The novel antipsychotic drug lurasidone enhances N-methyl-D-aspartate receptor-mediated synaptic responses. Mol Pharmacol. 2012;81:113–9. source
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In the paper
“Broadly disrupted DNA methylation profiles are also reported in SZ PFC 199.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [199] Lee SA, Huang KC. Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia. BMC Med Genomics. 2016;9:68. source
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In the paper
“Diminished expression of several synaptic genes, including CALM2, SYN1, RAB3A, RAB4B and TUBB4, is observed in PFC of MDD patients, along with reduced spine density in layers II/III of DLPFC 209.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [209] Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7. source
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In the paper
“MDD patients display the reduced glucose metabolism in DLPFC 204”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [204] Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989;46:243–50. source
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In the paper
“and the significantly reduced mPFC volume spanning across dorsomedial PFC, ventromedial (VM) PFC and ACC 205.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [205] Belleau EL, Treadway MT, Pizzagalli DA. The impact of stress and major depressive disorder on hippocampal and medial prefrontal cortex morphology. Biol Psychiatry. 2019;85:443–53. source
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In the paper
“which may underlie its effect on reversing cognitive impairment in SZ.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [195] Yuen EY, Li X, Wei J, Horiguchi M, Meltzer HY, Yan Z. The novel antipsychotic drug lurasidone enhances N-methyl-D-aspartate receptor-mediated synaptic responses. Mol Pharmacol. 2012;81:113–9. source
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In the paper
“In a rat model of SZ, abnormal epigenetic repression of the NMDAR subunit Grin2b in PFC drives glutamatergic synaptic deficits 201.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [201] Gulchina Y, Xu SJ, Snyder MA, Elefant F, Gao WJ. Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia. J Neurochem. 2017;143:320–33. source
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In the paper
“D1R activation in PFC facilitates the maintenance of long-term potentiation (LTP) of glutamatergic transmission, as well as the induction of long-term depression (LTD) of glutamatergic transmission, indicating its bidirectional modulation of synaptic plasticity in mPFC 189.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [189] Huang YY, Simpson E, Kellendonk C, Kandel ER. Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci USA. 2004;101:3236–41. source
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In the paper
“Substantial evidence indicates that mPFC dysfunction plays a critical role in the pathology of major depressive disorder (MDD) 203.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [203] Koenigs M, Grafman J. The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. Behavioural Brain Res. 2009;201:239–43. source
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In the paper
“The density of PNNs is also reduced in PFC of stressed mice 219 and rats 220”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [219] Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, et al. Juvenile stress induces behavioral change and affects perineuronal net formation in juvenile mice. BMC Neurosci. 2018;19:41. source
- Not checked yetcites [220] Yu Z, Chen N, Hu D, Chen W, Yuan Y, Meng S, et al. Decreased density of perineuronal net in prelimbic cortex is linked to depressive-like behavior in young-aged rats. Front Mol Neurosci. 2020;13:4. source
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In the paper
“However, deletion of the NMDAR subunit GluN2B from mPFC pyramidal neurons in vivo produces antidepressant-like effects, while also preventing ketamine’s effects on behavior, EPSC and the induction of mTOR activation in mouse mPFC 224”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [224] Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. elife. 2014;3:e03581. source
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In the paper
“Furthermore, direct activation of the mTORC1 pathway via NV-5138 produces antidepressant effects in rats, suggesting that mTORC1 activation alone may be sufficient to alleviate depressive symptoms 231.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [231] Hasegawa Y, Zhu X, Kamiya A. NV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling. J Clin Investig. 2019;129:2207–9. source
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In the paper
“NBQX treatment also prevents ketamine’s induction of mTOR signaling, suggesting that mTOR activation is mediated by AMPA receptor activation 227.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [227] Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29:419–23. source
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In the paper
“NBQX treatment also prevents ketamine’s induction of mTOR signaling, suggesting that mTOR activation is mediated by AMPA receptor activation 227.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [227] Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29:419–23. source
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In the paper
“RNA-seq of postmortem DLPFC tissue from individuals who died by suicide also revealed the downregulation of GABAAR γ2 subunit 215.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [215] Yin H, Pantazatos SP, Galfalvy H, Huang YY, Rosoklija GB, Dwork AJ, et al. A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:414–26. source
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In the paper
“The paradoxical increase in glutamate activity driven by ketamine initially appeared to be mediated by the loss of NMDA-mediated excitation of GABA interneurons, resulting in disinhibition of pyramidal neurons 170 (Fig. 4B).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [170] Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–11500. source
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In the paper
“Studies in mice indicate that scopolamine, an effective antidepressant medication acting on muscarinic acetylcholine receptors, enacts its antidepressant effects via targeting somatostatin-expressing GABAergic interneurons in mPFC 218”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [218] Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Investig. 2016;126:2482–94. source
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In the paper
“DNA methyltransferases have also been implicated in depression 234.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [234] Duan Z, Lu J. DNA Methyltransferases in depression: an update. Front Psychiatry. 2020;11:538683. source
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In the paper
“and its therapeutic efficacy appears to be dependent upon its effects on PFC, along with its connecting regions.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [221] Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509–23. source
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In the paper
“and the reduced surface expression of NMDA and AMPA receptor subunits in mPFC that could be restored via ketamine treatment 217”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [217] Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D, et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry. 2016;80:457–68. source
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In the paper
“further implicating the mTOR signaling pathway in MDD.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [229] Aguilar-Valles A, Haji N, De Gregorio D, Matta-Camacho E, Eslamizade MJ, Popic J, et al. Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nat Commun. 2018;9:2459. source
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In the paper
“suggesting that GABAergic impairment could affect glutamatergic signaling in MDD PFC.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [217] Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D, et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry. 2016;80:457–68. source
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In the paper
“Electrophysiological recordings similarly indicate that ketamine elevates the frequency of excitatory postsynaptic currents (EPSC) in mouse PFC pyramidal neurons 224.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [224] Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. elife. 2014;3:e03581. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, deletion of the NMDAR subunit GluN2B from mPFC pyramidal neurons in vivo produces antidepressant-like effects, while also preventing ketamine’s effects on behavior, EPSC and the induction of mTOR activation in mouse mPFC 224”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [224] Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. elife. 2014;3:e03581. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“suggesting that PNNs may be disrupted in MDD, similar to SZ.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [219] Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, et al. Juvenile stress induces behavioral change and affects perineuronal net formation in juvenile mice. BMC Neurosci. 2018;19:41. source
- Not checked yetcites [220] Yu Z, Chen N, Hu D, Chen W, Yuan Y, Meng S, et al. Decreased density of perineuronal net in prelimbic cortex is linked to depressive-like behavior in young-aged rats. Front Mol Neurosci. 2020;13:4. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, an optogenetic study reveals that activating D1R-, but not D2R-, expressing PFC pyramidal neurons produces rapid and long-lasting antidepressant and anxiolytic responses, and disruption of D1R activity blocks the rapid antidepressant effects of ketamine 212.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [212] Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun. 2019;10:223. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, direct activation of the mTORC1 pathway via NV-5138 produces antidepressant effects in rats, suggesting that mTORC1 activation alone may be sufficient to alleviate depressive symptoms 231.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [231] Hasegawa Y, Zhu X, Kamiya A. NV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling. J Clin Investig. 2019;129:2207–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The mTOR activation of BDNF and synaptogenesis in PFC appear to be involved in Ketamine’s therapeutic function, because transgenic mice carrying a mutant form of BDNF that cannot translocate to dendrites do not display ketamine-dependent synaptogenesis nor antidepressant-like behavioral responses 228.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [228] Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71:996–1005. source
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In the paper
“Interestingly, mice carrying heterozygous deficiency of the GABAAR γ2 subunit in forebrain display depression-like behavioral phenotypes 216”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [216] Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H, et al. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci. 2007;27:3845–54. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The mTOR activation of BDNF and synaptogenesis in PFC appear to be involved in Ketamine’s therapeutic function, because transgenic mice carrying a mutant form of BDNF that cannot translocate to dendrites do not display ketamine-dependent synaptogenesis nor antidepressant-like behavioral responses 228.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [228] Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71:996–1005. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The ketamine-induced elevation in PFC glutamate release promotes AMPA receptor activation, which is necessary for ketamine’s antidepressant effects; pre-administration of the AMPAR receptor antagonist NBQX prevents ketamine’s antidepressant-like behavioral effects in mice 226.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [226] Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–52. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Additionally, protein levels of GAD67, the primary enzyme responsible for GABA synthesis, are reduced in MDD PFC, and PET imaging studies reveal lower GABA levels in PFC of MDD patients 214.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [214] Fogaca MV, Duman RS. Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions. Front Cell Neurosci. 2019;13:87. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, an optogenetic study reveals that activating D1R-, but not D2R-, expressing PFC pyramidal neurons produces rapid and long-lasting antidepressant and anxiolytic responses, and disruption of D1R activity blocks the rapid antidepressant effects of ketamine 212.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [212] Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun. 2019;10:223. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“HDAC inhibitor produces antidepressant-like effects in mice 233.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [233] Schroeder FA, Lin CL, Crusio WE, Akbarian S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry. 2007;62:55–64. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Additionally, protein levels of GAD67, the primary enzyme responsible for GABA synthesis, are reduced in MDD PFC, and PET imaging studies reveal lower GABA levels in PFC of MDD patients 214.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [214] Fogaca MV, Duman RS. Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions. Front Cell Neurosci. 2019;13:87. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Mice expressing a non-phosphorylatable mutant copy of the signaling molecule eIF4E (eukaryotic initiation factor 4E), which is activated downstream of mTORC1, display depression-like behaviors 229”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [229] Aguilar-Valles A, Haji N, De Gregorio D, Matta-Camacho E, Eslamizade MJ, Popic J, et al. Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nat Commun. 2018;9:2459. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Microarray analyses of PFC tissue from MDD patients indicate the downregulation of genes related to GABAergic signaling, including multiple GABAA receptor subunits 213.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [213] Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, ffrench-Mullen J, et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry. 2009;14:175–89. source
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In the paper
“In human MDD patients, ketamine administration similarly increases glutamate/glutamine cycling in PFC 225.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [225] Abdallah CG, De Feyter HM, Averill LA, Jiang L, Averill CL, Chowdhury GMI, et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 2018;43:2154–60. source
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In the paper
“In addition to the disrupted glutamatergic transmission, there is also evidence for GABAergic impairment in MDD.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [213] Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, ffrench-Mullen J, et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry. 2009;14:175–89. source
- Not checked yetcites [214] Fogaca MV, Duman RS. Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions. Front Cell Neurosci. 2019;13:87. source
- Not checked yetcites [215] Yin H, Pantazatos SP, Galfalvy H, Huang YY, Rosoklija GB, Dwork AJ, et al. A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:414–26. source
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In the paper
“Notably, the significantly reduced protein expression level of mTOR and several downstream signaling molecules is reported in postmortem PFC tissue from depressed patients 112.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [112] Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA, et al. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35:1774–9. source
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In the paper
“mTOR inhibition is sufficient to prevent the ketamine-dependent induction of synaptogenesis in PFC and antidepressant-like behavioral effects in rats 113.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [113] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
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In the paper
“suggesting that ketamine enacts direct effects on pyramidal neurons via GluN2B antagonism.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [224] Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. elife. 2014;3:e03581. source
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In the paper
“The NMDAR antagonist ketamine produces rapid antidepressant effects in those with treatment-resistant depression 221”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [221] Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509–23. source
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In the paper
“These findings suggest that pharmacological targeting of epigenetic enzymes may be a novel treatment strategy for depressive symptoms.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent study has found that β-amyloid oligomers bind to an allosteric site on α2-ARs to redirect norepinephrine signaling to activate the pathogenic GSK3β/tau cascade 250.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [250] Zhang F, Gannon M, Chen Y, Yan S, Zhang S, Feng W, et al. β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Sci Transl Med. 2020;12:eaay6931. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both AD patients and symptomatic AD mouse models show impaired synaptic plasticity in PFC, which is related to the impaired NMDAR function 255.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [255] Battaglia F, Wang HY, Ghilardi MF, Gashi E, Quartarone A, Friedman E, et al. Cortical plasticity in Alzheimer’s disease in humans and rodents. Biol Psychiatry. 2007;62:1405–12. source
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In the paper
“suggesting that these PFC synaptic markers are predictive molecular fingerprint for neurodegenerative diseases”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [253] Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobágyi T, et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain. 2018;141:582–95. source
- Not checked yetcites [254] Bereczki E, Francis PT, Howlett D, Pereira JB, Höglund K, Bogstedt A, et al. Synaptic proteins predict cognitive decline in Alzheimer’s disease and Lewy body dementia. Alzheimer’s Dement: J Alzheimer’s Assoc. 2016;12:1149–58. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The diminished transcription of NMDA and AMPA receptors in late-stage AD mouse models has been linked to the EHMT1/2-mediated repressive histone methylation at their promoters 256.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [256] Zheng Y, Liu A, Wang ZJ, Cao Q, Wang W, Lin L, et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain. 2019;142:787–807. source
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In the paper
“In aged PFC, the cAMP/PKA pathway is disinhibited, and PKA inhibition provides an effective approach for treating age-related cognitive decline 237.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [237] Ramos BP, Birnbaum SG, Lindenmayer I, Newton SS, Duman RS, Arnsten AF. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron. 2003;40:835–45. source
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In the paper
“The loss of thin spines in monkey PFC, which are particularly plastic and linked to learning, is selectively correlated with age-related cognitive impairment 241.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [241] Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, et al. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci. 2010;30:7507–15. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“AChE inhibitors produce a strong and persistent reduction of synaptic NMDAR responses in PFC pyramidal neurons via nicotinic ACh receptors 243.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [243] Chen G, Chen P, Tan H, Ma D, Dou F, Feng J, et al. Regulation of the NMDA receptor-mediated synaptic response by acetylcholinesterase inhibitors and its impairment in an animal model of Alzheimer’s disease. Neurobiol aging. 2008;29:1795–804. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ-induced loss of RACK1 (an anchoring protein for activated PKC) distribution in the membrane fraction of cortical neurons is found to underlie the impairment of muscarinic regulation of PKC 247.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [247] Liu W, Dou F, Feng J, Yan Z. RACK1 is involved in н╡-amyloid impairment of muscarinic regulation of GABAergic transmission. Neurobiol Aging. 2011;32:1818–26. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition to the downregulation of genes involved in synaptic transmission and synapse organization, there is also prominent upregulation of genes involved in cell stress, immune response activation and cell death in PFC of AD patients 257–259.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [257] Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–7. source
- Not checked yetcites [258] Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153:707–20. source
- Not checked yetcites [259] Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med. 2020;26:131–42. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In aged PFC, the cAMP/PKA pathway is disinhibited, and PKA inhibition provides an effective approach for treating age-related cognitive decline 237.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [237] Ramos BP, Birnbaum SG, Lindenmayer I, Newton SS, Duman RS, Arnsten AF. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron. 2003;40:835–45. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Activation of muscarinic or nicotinic ACh receptors in PFC pyramidal neurons also enhances inhibitory synaptic transmission through PKC-dependent mechanisms 244,245.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [244] Ma XH, Zhong P, Gu Z, Feng J, Yan Z. Muscarinic potentiation of GABA(A) receptor currents is gated by insulin signaling in the prefrontal cortex. J Neurosci. 2003;23:1159–68. source
- Not checked yetcites [245] Chen GJ, Xiong Z, Yan Z. Aβ impairs nicotinic regulation of inhibitory synaptic transmission and interneuron excitability in prefrontal cortex. Mol Neurodegeneration. 2013;8:3. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies suggest that restoring cholinergic regulation of PFC synaptic activity and neuronal excitability might help to treat AD-associated cognitive disorders.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ infused into the monkey brain induces accelerated cortical aging by triggering the specific loss of dendritic thin spines in the PFC 242.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [242] Beckman D, Ott S, Donis-Cox K, Janssen WG, Bliss-Moreau E, Rudebeck PH, et al. Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging. Proc Natl Acad Sci USA. 2019;116:26239–46. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, systemic administration of DNA methyltransferase inhibitors induces antidepressant-like effects in rats 236.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [236] Sales AJ, Biojone C, Terceti MS, Guimaraes FS, Gomes MV, Joca SR. Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors. Br J Pharm. 2011;164:1711–21. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Systematic search for global gene expression changes in PFC during the course of AD has found a temporally orchestrated increase of genes involved in synaptic activity during the very early pre-symptomatic stage, probably representing a coping mechanism against increased β-amyloid levels, and the decreased expression of these synaptic genes in later Braak stages, suggesting a reduction in synaptic”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [252] Bossers K, Wirz KT, Meerhoff GF, Essing AH, van Dongen JW, Houba P, et al. Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain. 2010;133:3699–723. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The cholinergic regulation of NMDA and GABA function is impaired in transgenic mice overexpressing mutant β-amyloid precursor protein (APP) 243,245,246.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [243] Chen G, Chen P, Tan H, Ma D, Dou F, Feng J, et al. Regulation of the NMDA receptor-mediated synaptic response by acetylcholinesterase inhibitors and its impairment in an animal model of Alzheimer’s disease. Neurobiol aging. 2008;29:1795–804. source
- Not checked yetcites [245] Chen GJ, Xiong Z, Yan Z. Aβ impairs nicotinic regulation of inhibitory synaptic transmission and interneuron excitability in prefrontal cortex. Mol Neurodegeneration. 2013;8:3. source
- Not checked yetcites [246] Zhong P, Gu Z, Wang X, Jiang H, Feng J, Yan Z. Impaired modulation of GABAergic transmission by muscarinic receptors in a mouse transgenic model of Alzheimer’s disease. J Biol Chem. 2003;278:26888–96. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The brain noradrenergic system is also critical for cognition and noradrengergic dysfunction is a critical early step in AD progression 249.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [249] Rorabaugh JM, Chalermpalanupap T, Botz-Zapp CA, Fu VM, Lembeck NA, Cohen RM, et al. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease. Brain. 2017;140:3023–38. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The marked loss of PFC persistent firing in aged monkeys is also partially restored by inhibiting cAMP signaling or blocking HCN or KCNQ channels 238.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [238] Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, et al. Neuronal basis of age-related working memory decline. Nature. 2011;476:210–3. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Age-related increase in PKA phosphorylation of tau at serine 214 in monkey PFC is thought to confer risk for degeneration of glutamatergic synapses 239.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [239] Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE, Simen AA, et al. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc Natl Acad Sci USA. 2014;111:5036–41. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Studies of postmortem human brains have found the significant association between cognitive decline and the loss of synaptic proteins in PFC, such as SNAP25, SNAP47, SV2C, SYT2 and GRIA3 253,254”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [253] Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobágyi T, et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain. 2018;141:582–95. source
- Not checked yetcites [254] Bereczki E, Francis PT, Howlett D, Pereira JB, Höglund K, Bogstedt A, et al. Synaptic proteins predict cognitive decline in Alzheimer’s disease and Lewy body dementia. Alzheimer’s Dement: J Alzheimer’s Assoc. 2016;12:1149–58. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“One of the top-ranking genes elevated by the abnormally high H3K4me3 in PFC of AD patients and mouse models is SGK1, which encodes the stress-responsive kinase SGK1.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [260] Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6:eabc8096. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Overwhelming evidence has indicated that PFC is a uniquely important brain region for the highest level of excecutive function, which drives self-regulatory and goal-directed behaviors 261–263.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Concluding Remarks
What the sources say
- Not checked yetcites [261] McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79:16–29. source
- Not checked yetcites [262] Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011;13:22–37. source
- Not checked yetcites [263] Arnsten AF. Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci. 2015;18:1376–85. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Dysregulation of PFC synaptic transmission directly contributes to the impairment of social, affective, motivational, and cognitive function associated with brain disorders including autism, schizophrenia, depression and Alzheimer’s disease.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Concluding Remarks
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that targeting histone methylation enzymes may represent a novel therapeutic avenue for normalizing the aberrant epigenetic regulation of gene transcription in PFC that underlies cognitive deficits in AD.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 79
- Probably not a substantial claim. 7
Every source the paper cites for this claim was checked and supports it.
In the paper
“Prefrontal circuitry can dynamically control reward-seeking behaviour through projection-specific cue encoding 16: stimulation of PFC to nucleus accumbens (NAc) neurons promotes conditioned reward-seeking behaviour, while activation of PFC to thalamic neurons suppresses both the acquisition and expression of conditioned reward seeking.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Supportedcites [16] Otis JM, Namboodiri VM, Matan AM, Voets ES, Mohorn EP, Kosyk O, et al. Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature. 2017;543:103–7. source
The Letter reports that activating PFC-NAc neurons increased anticipatory licking after conditioning (Fig. 5), supporting the claim about expression of reward seeking. It also reports that activating PFC-PVT neurons reduced anticipatory licking both in a no-laser test of acquisition (Fig. 4) and after conditioning (Fig. 5). (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In contrast to the positive effects of acute stress, chronic stress (e.g. 21-day restraint stress) produces impaired dendritic branching, atrophy and spine loss in PFC pyramidal neurons 102,105, and such structural reorganization is reversed after 3-week cessation of stress 106.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Partly supportedcites [102] Musazzi L, Treccani G, Popoli M. Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress. Front Psychiatry. 2015;6:60. sourceExperimental — accuracy not yet measured
The section on morphological changes and Table 1 report reduced dendritic branching, atrophy, and spine density in PFC pyramidal neurons after chronic stress, including 21-day restraint stress. The copy cites a study titled “Reversibility of apical dendritic retraction,” but does not state that the structural changes reversed after three weeks without stress. (LLM, conf=0.86)
- Not checked yetcites [105] Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20. source
- Not checked yetcites [106] Radley JJ, Rocher AB, Janssen WG, Hof PR, McEwen BS, Morrison JH. Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress. Exp Neurol. 2005;196:199–203. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“In parallel with these neurophysiological studies, neuroimaging studies also implicate the human PFC in higher-order cognitive processing including working memory 9 and sustained attention 10.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [9] McCarthy G, Blamire AM, Puce A, Nobre AC, Bloch G, Hyder F, et al. Functional magnetic resonance imaging of human prefrontal cortex activation during a spatial working memory task. Proc Natl Acad Sci USA. 1994;91:8690–4. source
- Not checked yetcites [10] Pardo JV, Fox PT, Raichle ME. Localization of a human system for sustained attention by positron emission tomography. Nature. 1991;349:61–64. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PFC fast spiking (FS) interneurons (presumably expressing parvalbumin, PV+) form contacts on the perisomatic domains of pyramidal neurons, while non-FS interneurons (presumably expressing somatostatin, SST+) contact peridendritic domains 28, enabling PV+ and SST+ interneurons to specialize in the control of the output and input of principal neurons, respectively.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [28] Gao WJ, Wang Y, Goldman-Rakic PS. Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex. J Neurosci. 2003;23:1622–30. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In monkey PFC neurons, the rapid phase of synaptogenesis reaches the plateau at 2 months old, and maintains the consistently high synaptic density from early adolescence through puberty (2 months to 3 years), the formative time when learning experiences are most intense 1.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [1] Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;4:78–96. source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Thalamic input amplifies PFC connectivity, sustaining attentional control 24 and enabling sensory selection in divided attention 25.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [24] Schmitt LI, Wimmer RD, Nakajima M, Happ M, Mofakham S, Halassa MM. Thalamic amplification of cortical connectivity sustains attentional control. Nature. 2017;545:219–23. source
- Not checked yetcites [25] Wimmer RD, Schmitt LI, Davidson TJ, Nakajima M, Deisseroth K, Halassa MM. Thalamic control of sensory selection in divided attention. Nature. 2015;526:705–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Based on anatomical, functional and connectivity homologies, it is thought that rodent PFC is composed of three cytoarchitecturally defined parts: the prelimbic (PL), infralimbic (IL), and anterior cingulate cortex (ACC) 11,12.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [11] Uylings HB, Groenewegen HJ, Kolb B. Do rats have a prefrontal cortex? Behavioural Brain Res. 2003;146:3–17. source
- Not checked yetcites [12] Ongür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10:206–19. source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The neural projection from medial PFC (mPFC) to a brainstem area has been found to control behavioral adaptation to social defeat 19: social defeat weakens functional connectivity of these two areas, while selective inhibition of this pathway recaptures behavioral effects of social defeat.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [19] Franklin TB, Silva BA, Perova Z, Marrone L, Masferrer ME, Zhan Y, et al. Prefrontal cortical control of a brainstem social behavior circuit. Nat Neurosci. 2017;20:260–70. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Tracing studies have found that deep layer PFC pyramidal neurons project to mediodorsal thalamus, lateral hypothalamus, ventral and dorsal striatum, and basolateral amygdala (BLA) 15.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [15] Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ. Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol. 2005;492:145–77. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PV+ interneurons, which could fire in millisecond synchrony, exert fast and powerful inhibition on principal neuron firing, whereas SST+ interneurons exert weak and more variable inhibitory effects on firing output in behaving mice 29.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [29] Kvitsiani D, Ranade S, Hangya B, Taniguchi H, Huang JZ, Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature. 2013;498:363–6. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The direct hippocampal to prefrontal afferents in mice are found to be critical for encoding of spatial cues during working memory, and successful encoding of task-related information is mediated by gamma-frequency synchrony between hippocampus and PFC 21.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC network organization and functional implications
What the sources say
- Not checked yetcites [21] Spellman T, Rigotti M, Ahmari SE, Fusi S, Gogos JA, Gordon JA. Hippocampal-prefrontal input supports spatial encoding in working memory. Nature. 2015;522:309–14. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It suggests that optimal levels of dopamine are essential for PFC function, while excessive dopamine stimulation could be detrimental.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Dampening thalamic activity causes significant reductions of GABA signaling in the mPFC and concomitant abnormalities in cognition and social interaction, which is ameliorated by selectively activating mPFC PV+ interneurons 34.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [34] Ferguson BR, Gao WJ. Thalamic control of cognition and social behavior via regulation of gamma-aminobutyric acidergic signaling and excitation/inhibition balance in the medial prefrontal cortex. Biol Psychiatry. 2018;83:657–69. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Dopamine has no effect on excitatory transmission from pyramidal neurons to FS interneurons, but increases the excitability of FS interneurons 52.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [52] Gao WJ, Goldman-Rakic PS. Selective modulation of excitatory and inhibitory microcircuits by dopamine. Proc Natl Acad Sci USA. 2003;100:2836–41. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In mice performing a reward foraging task, SST+ interneurons in ACC are found to selectively respond at reward approach, whereas PV+ interneurons respond at reward leaving 29.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [29] Kvitsiani D, Ranade S, Hangya B, Taniguchi H, Huang JZ, Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature. 2013;498:363–6. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“suggesting that SST+ interneurons are uniquely involved in facilitating hippocampal-prefrontal synchrony and prefrontal spatial encoding.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [39] Abbas AI, Sundiang MJM, Henoch B, Morton MP, Bolkan SS, Park AJ, et al. Somatostatin interneurons facilitate hippocampal-prefrontal synchrony and prefrontal spatial encoding. Neuron. 2018;100:926–39.e923. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Blocking dopamine receptor activation in PFC shortens the VTA excitation of PFC PV+ interneurons and prolongs the VTA excitation of PFC principal neurons”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [55] Zhong P, Qin L, Yan Z. Dopamine differentially regulates response dynamics of prefrontal cortical principal neurons and interneurons to optogenetic stimulation of inputs from ventral tegmental area. Cereb Cortex. 2020;30:4402–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“PV+ and SST+ interneurons in mPFC are also found to have distinct roles in WM: PV interneurons show weak target-dependent delay-period activity and are strongly inhibited by reward; while SST+ interneurons show strong target-dependent delay-period activity, and only a subtype of them is inhibited by reward 41.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [41] Kim D, Jeong H, Lee J, Ghim JW, Her ES, Lee SH, et al. Distinct roles of parvalbumin- and somatostatin-expressing interneurons in working memory. Neuron. 2016;92:902–15. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Optogenetic stimulation of VTA neurons to trigger the synaptically released dopamine has revealed a marked and prolonged enhancement of the excitability of PFC PV+ interneurons and a modest and short-lived enhancement of the excitability of PFC principal neurons 55.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [55] Zhong P, Qin L, Yan Z. Dopamine differentially regulates response dynamics of prefrontal cortical principal neurons and interneurons to optogenetic stimulation of inputs from ventral tegmental area. Cereb Cortex. 2020;30:4402–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“SST+ interneurons in mPFC of mice are found to play a primary role in orchestrating the ability to discriminate positive and negative affective states 38: inhibition of mPFC SST+ interneurons abolishes affective state discrimination, while an increased synchronous activity of PFC SST+ interneurons, which guides the inhibition of PFC pyramidal neurons, is associated with this social cognitive funct”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [38] Scheggia D, Managò F, Maltese F, Bruni S, Nigro M, Dautan D, et al. Somatostatin interneurons in the prefrontal cortex control affective state discrimination in mice. Nat Neurosci. 2020;23:47–60. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In mice performing a PFC-dependent sensory discrimination task, PV+ interneurons are responsive to sensory cues, motor action, and trial outcomes, while SST+ and VIP+ interneurons respond more selectively to motor action or trial outcomes, respectively, and pyramidal neurons show much greater functional heterogeneity with varied responses across cortical layers 37.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [37] Pinto L, Dan Y. Cell-type-specific activity in prefrontal cortex during goal-directed behavior. Neuron. 2015;87:437–50. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Serial section electron microscopy studies suggest that the majority of dopamine synapses in all PFC layers are on pyramidal neurons, but a significant fraction are on GABAergic interneurons 49.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [49] Smiley JF, Goldman-Rakic PS. Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver-enhanced diaminobenzidine sulfide (SEDS) immunolabeling technique. Cereb Cortex. 1993;3:223–38. source
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Inhibiting PFC pyramidal neurons by optogenetically activating SST+ or PV+ interneurons during the delay impairs working memory performance, while activating VIP+ interneurons in PFC improves memory retention 40”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [40] Kamigaki T, Dan Y. Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior. Nat Neurosci. 2017;20:854–63. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stimulation of α2A-ARs enhances the spatially-tuned, delay-related firing of PFC neurons and strengthens working memory networks through inhibition of cAMP and closing HCN (Hyperpolarization-activated Cyclic Nucleotide-gated) channels 71.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Noradrenaline
What the sources say
- Not checked yetcites [71] Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“High levels of D1R activation of cAMP signaling reduces PFC neuronal firing and impairs working memory via opening of HCN channels at excitatory synapses 54.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [54] Gamo NJ, Lur G, Higley MJ, Wang M, Paspalas CD, Vijayraghavan S, et al. Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels. Biol Psychiatry. 2015;78:860–70. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“During a spatial WM task, optogenetically inhibiting PFC SST+, but not PV+, interneurons decreases the long-range synchrony between hippocampus and PFC and impairs working memory accuracy 39”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Organization and Function > PFC cellular components and synaptic circuits
What the sources say
- Not checked yetcites [39] Abbas AI, Sundiang MJM, Henoch B, Morton MP, Bolkan SS, Park AJ, et al. Somatostatin interneurons facilitate hippocampal-prefrontal synchrony and prefrontal spatial encoding. Neuron. 2018;100:926–39.e923. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“DA depressed inhibitory transmission between FS interneurons and pyramidal neurons, but enhanced inhibition between non-FS interneurons and pyramidal cells 28.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Dopamine
What the sources say
- Not checked yetcites [28] Gao WJ, Wang Y, Goldman-Rakic PS. Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex. J Neurosci. 2003;23:1622–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Endogenous norepinephrine (NE, also called noradrenaline), by acting on α1-ARs, exerts complex effects in PFC: NE increases the firing of some PFC pyramidal neurons via presynaptic excitation of glutamate release under basal conditions, but when high levels of α1-AR stimulation occurs, such as with stress exposure, NE suppresses PFC neuronal firing through opening of K+ channels on spines 70.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Noradrenaline
What the sources say
- Not checked yetcites [70] Datta D, Yang ST, Galvin VC, Solder J, Luo F, Morozov YM, et al. Noradrenergic α1-adrenoceptor actions in the primate dorsolateral prefrontal cortex. J Neurosci. 2019;39:2722–34. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced catecholamine transmission has been linked to ADHD, while overamplified noradrenergic transmission is associated with PTSD 46.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Regulation of PFC Synaptic Function > Monoaminergic regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [46] Arnsten AF. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011;69:e89–99. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Interestingly, reduced SGK expression is found in postmortem brains of PTSD patients, and inhibition of SGK in rat PFC produces helplessness- and anhedonia-like phenotypes 100.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [100] Licznerski P, Duric V, Banasr M, Alavian KN, Ota KT, Kang HJ, et al. Decreased SGK1 expression and function contributes to behavioral deficits induced by traumatic stress. PLoS Biol. 2015;13:e1002282. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“VGF in PFC regulates susceptibility to stress and the antidepressant response to ketamine, and infusion of VGF C-terminal peptide TLQP-62 to PFC produces sustained antidepressant responses 116.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Neuropeptides
What the sources say
- Not checked yetcites [116] Jiang C, Lin WJ, Labonté B, Tamminga CA, Turecki G, Nestler EJ, et al. VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine. Neuropsychopharmacology. 2019;44:971–81. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Glucocorticoid receptor (GR) knockdown in IL induces compromised stress adaptation and depression-like behavior, while GR knockdown in PL increases HPA axis responses to acute stress but does not affect stress sensitization or helplessness behavior 93”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [93] McKlveen JM, Myers B, Flak JN, Bundzikova J, Solomon MB, Seroogy KB, et al. Role of prefrontal cortex glucocorticoid receptors in stress and emotion. Biol Psychiatry. 2013;74:672–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“It has been found that 5-HT1A receptors in PFC pyramidal neurons suppress NMDAR function by disrupting the microtubule/kinesin-based dendritic transport of NMDA receptors 83, while this effect of 5-HT1A is opposed by 5-HT2A/C signaling 82.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin
What the sources say
- Not checked yetcites [83] Yuen EY, Jiang Q, Chen P, Gu Z, Feng J, Yan Z. Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci. 2005;25:5488–501. source
- Not checked yetcites [82] Yuen EY, Jiang Q, Chen P, Feng J, Yan Z. Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex. J Biol Chem. 2008;283:17194–204. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“NPY in IL cortex, acting on NPY Y1 receptors, increases inhibitory synaptic transmission onto IL projection neurons and dampens their excitability, resulting in the significant impairment of fear extinction memory 117.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Neuropeptides
What the sources say
- Not checked yetcites [117] Vollmer LL, Schmeltzer S, Schurdak J, Ahlbrand R, Rush J, Dolgas CM, et al. Neuropeptide Y impairs retrieval of extinguished fear and modulates excitability of neurons in the infralimbic prefrontal cortex. J Neurosci. 2016;36:1306–15. source
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In the paper
“REDD1, an endogenous inhibitor of mTOR, shows the elevated expression in PFC of animals exposed to chronic unpredictable stress and PFC of post-partum depressed humans 114.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [114] Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, et al. REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat Med. 2014;20:531–5. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Decreased levels of mTORC are found in PFC of humans with major depressive disorder 112, and the fast-acting antidepressant ketamine increases mTORC signaling in rat PFC 113.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [112] Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA, et al. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35:1774–9. source
- Not checked yetcites [113] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, acute footshock stress increases spine density and induces dendritic remodeling in medial PFC, which can be partially blocked by chronic treatment with the antidepressant desipramine 102,103.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [102] Musazzi L, Treccani G, Popoli M. Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress. Front Psychiatry. 2015;6:60. source
- Not checked yetcites [103] Nava N, Treccani G, Liebenberg N, Chen F, Popoli M, Wegener G, et al. Chronic desipramine prevents acute stress-induced reorganization of medial prefrontal cortex architecture by blocking glutamate vesicle accumulation and excitatory synapse increase. Int J Neuropsychopharmacol. 2014;18:pyu085.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampus-PFC connection 107, and repeated social stress during mid-adolescence significantly decreases synaptic activity and intrinsic excitability of mPFC neurons 108.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin > Hormonal regulation of PFC synaptic transmission
What the sources say
- Not checked yetcites [107] Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci. 2007;27:2781–7. source
- Not checked yetcites [108] Urban KR, Valentino RJ. Age- and sex-dependent impact of repeated social stress on intrinsic and synaptic excitability of the rat prefrontal cortex. Cereb Cortex. 2017;27:244–53.
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In the paper
“Reduced levels of VGF have been found in PFC of MDD patients and PFC of chronically stressed mice 116.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Neuropeptides
What the sources say
- Not checked yetcites [116] Jiang C, Lin WJ, Labonté B, Tamminga CA, Turecki G, Nestler EJ, et al. VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine. Neuropsychopharmacology. 2019;44:971–81. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“At thalamocortical synapses, 5-HT2A activation enhances NMDA transmission, gates the induction of NMDAR-mediated temporal plasticity, and facilitates associated cognitive functions 91.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin
What the sources say
- Not checked yetcites [91] Barre A, Berthoux C, De Bundel D, Valjent E, Bockaert J, Marin P, et al. Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning. Proc Natl Acad Sci USA. 2016;113:E1382–1391. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“5-HT2 receptors inhibit GABAAR-mediated currents in PFC pyramidal neurons through phosphorylation of GABAA receptors by the activation of anchored PKC 87, while 5-HT4 receptors modulate GABAergic signaling bi-directionally, depending on the basal PKA activation levels that are determined by neuronal activity 80.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Serotonin
What the sources say
- Not checked yetcites [87] Feng J, Cai X, Zhao J, Yan Z. Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci. 2001;21:6502–11. source
- Not checked yetcites [80] Cai X, Flores-Hernandez J, Feng J, Yan Z. Activity-dependent bidirectional regulation of GABA(A) receptor channels by the 5-HT(4) receptor-mediated signalling in rat prefrontal cortical pyramidal neurons. J Physiol. 2002;540:743–59. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Transcriptomic meta-analyses of human cerebral cortex across major neuropsychiatric disorders, including autism (ASD), schizophrenia (SZ), bipolar disorder (BD) and depression (MDD), have found the shared transcriptional dysregulation underlying convergent molecular neuropathology, such as a gradient of synaptic gene down-regulation and astroglial gene up-regulation in ASD, SZ and BD (ASD > SZ = B”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > PFC Dysregulation and Diseases
What the sources say
- Not checked yetcites [120] Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–7. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Chemogenetic activation of PFC pyramidal neurons in Shank3-deficient mice also restores social preference behaviors and elevates glutamatergic synaptic function 129.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [129] Qin L, Ma K, Yan Z. Chemogenetic activation of prefrontal cortex in Shank3-deficient mice ameliorates social deficits, NMDAR hypofunction, and Sgk2 downregulation. iScience. 2019;17:24–35. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Inhibition of EHMT1/2 rescues social deficits and restores PFC NMDAR function in Shank3-deficient mice via restoring the expression of plasticity gene Arc, which encodes the activity-regulated cytoskeleton-associated protein Arc 146.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [146] Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, et al. Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Mol Psychiatry. 2019;25:2517–33. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chemogenetic activation of PFC pyramidal neurons leads to the amelioration of cognitive and social impairments and the restoration of NMDAR function in 16p11+/− mice 133.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [133] Wang W, Rein B, Zhang F, Tan T, Zhong P, Qin L, et al. Chemogenetic activation of prefrontal cortex rescues synaptic and behavioral deficits in a mouse model of 16p11.2 deletion syndrome. J Neurosci. 2018;38:5939–48. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Systemic administration of the class I HDAC inhibitor romidepsin or MS-275 leads to the robust and persistent alleviation of social deficits, as well as the restoration of actin regulators and NMDAR function in PFC 144,145.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [144] Ma K, Qin L, Matas E, Duffney LJ, Liu A, Yan Z. Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism. Neuropsychopharmacology. 2018;43:1779–88. source
- Not checked yetcites [145] Qin L, Ma K, Wang ZJ, Hu Z, Matas E, Wei J, et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci. 2018;21:564–75. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, the reduced synaptic plasticity in hippocampus-mPFC pathway and impaired social recognition memory and attention in Shank3-deficient rats are attenuated by oxytocin treatment 130.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [130] Harony-Nicolas H, Kay M, du Hoffmann J, Klein ME, Bozdagi-Gunal O, Riad M, et al. Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. eLife. 2017;6:e18904. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Loss of Cul3 in forebrain or PFC leads to social deficits and NMDAR hypofunction, while loss of Cul3 in striatum leads to stereotypic behaviors and cell type-specific alteration of neuronal excitability in striatal circuits 147.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [147] Rapanelli M, Tan T, Wang W, Wang X, Wang ZJ, Zhong P, et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry 2019. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Inhibition or knockdown of Smyd3 ameliorates social deficits and restores PFC NMDAR function in forebrain Cul3-deficient mice 147.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [147] Rapanelli M, Tan T, Wang W, Wang X, Wang ZJ, Zhong P, et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry 2019. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In PFC of Shank3-deficient mice, the loss of histone acetylation and upregulation of HDAC2 have been identified 145.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [145] Qin L, Ma K, Wang ZJ, Hu Z, Matas E, Wei J, et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat Neurosci. 2018;21:564–75. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Inhibiting cofilin or activating Rac1 rescues the social deficits and NMDAR hypofunction in Shank3-deficient mice 127”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [127] Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400–13. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Restoring the expression of Npas4, a key regulator of GABA synapses 135,136, ameliorates the social and cognitive deficits, as well as GABAergic synaptic impairment and neuronal hyperexcitability in 16p11dp/+ mice 134.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [134] Rein B, Tan T, Yang F, Wang W, Williams J, Zhang F, et al. Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry. 2020; (e-pub ahead of print). source
- Not checked yetcites [135] Bloodgood BL, Sharma N, Browne HA, Trepman AZ, Greenberg ME. The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature. 2013;503:121–5. source
- Not checked yetcites [136] Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC, Kim TK, et al. Activity-dependent regulation of inhibitory synapse development by Npas4. Nature. 2008;455:1198–204. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“On the other hand, a 16p11.2 duplication mouse model, 16p11dp/+, exhibits deficient GABAergic synaptic transmission and elevated excitability in PFC pyramidal neurons 134.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [134] Rein B, Tan T, Yang F, Wang W, Williams J, Zhang F, et al. Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry. 2020; (e-pub ahead of print). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In PFC pyramidal neurons of Shank3-deficient mice, NMDAR function and synaptic distribution are significantly diminished, which is caused by a marked loss of actin filaments at glutamatergic synapses due to the altered Rac1/PAK/cofilin signaling 127.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [127] Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400–13. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“SZ has been linked to both aberrant PFC development during embryonic stages and disrupted PFC maturation in later adolescence driven by environmental stressors, making SZ a unique disorder with two critical susceptibility periods 151.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [151] Selemon LD, Zecevic N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry. 2015;5:e623. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Loss of Cul3 in forebrain or PFC leads to social deficits and NMDAR hypofunction, while loss of Cul3 in striatum leads to stereotypic behaviors and cell type-specific alteration of neuronal excitability in striatal circuits 147.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Autism
What the sources say
- Not checked yetcites [147] Rapanelli M, Tan T, Wang W, Wang X, Wang ZJ, Zhong P, et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry 2019. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“the reduced PV expression is reported both at the individual cellular level 181 and specifically within presynaptic boutons of PV+ basket cells 182.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [181] Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23:6315–26. source
- Not checked yetcites [182] Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry. 2014;19:30–36. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In rats treated with NMDAR antagonists, PFC neurons display the elevated and irregular spiking activity and the reduced coordinated burst firing, suggesting that NMDA hypofunction in PFC may drive disorganized network activity 174.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [174] Jackson ME, Homayoun H, Moghaddam B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci USA. 2004;101:8467–72. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“NMDAR-mediated connectivity between PFC and hippocampus is impaired in SZ, which is suggested as a mechanism underlying working memory deficits 167.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [167] Banks PJ, Burroughs AC, Barker GR, Brown JT, Warburton EC, Bashir ZI. Disruption of hippocampal-prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission. Proc Natl Acad Sci USA. 2015;112:11096–101. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“including the decreased GAD67 expression and reduced gamma oscillations, suggesting deficient GABA synthesis and GABAergic synaptic transmission, respectively 180.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [180] Lewis DA, Fish KN, Arion D, Gonzalez-Burgos G. Perisomatic inhibition and cortical circuit dysfunction in schizophrenia. Curr Opin Neurobiol. 2011;21:866–72. source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Proteomic analysis of SZ DLPFC samples identified 15 differentially expressed proteins, 7 of which were synaptic 164.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [164] Pennington K, Beasley CL, Dicker P, Fagan A, English J, Pariante CM, et al. Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder. Mol Psychiatry. 2008;13:1102–17. source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“There is strong support for NMDA hypofunction in SZ, as treatment with NMDAR antagonists, such as MK-801 or phencyclidine, can induce SZ-like symptoms in both human subjects 165 and in animals 166.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [165] Nakazawa K, Jeevakumar V, Nakao K. Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia. npj Schizophr. 2017;3:7. source
- Not checked yetcites [166] Kehrer C, Maziashvili N, Dugladze T, Gloveli T. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia. Front Mol Neurosci. 2008;1:6. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Blocking NMDARs with MK-801 injection leads to the impairment of mPFC-dependent cognitive flexibility and hippocampus-mPFC pathway-dependent spatial working memory 168.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [168] Blot K, Kimura S, Bai J, Kemp A, Manahan-Vaughan D, Giros B, et al. Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801. Cereb Cortex. 2015;25:1348–61. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MDD is associated with aberrant synaptic transmission in PFC, affecting both GABA and glutamate systems (Fig. 4B).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Computational models predict that an imbalance of D1R/D2R activation in the PFC may underlie the associated cognitive, positive and negative symptoms of SZ 190.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [190] Durstewitz D, Seamans JK. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol Psychiatry. 2008;64:739–49. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A meta-analysis of GWAS studies identified 102 genetic risk variants in MDD patients, many of which display high expression in frontal cortex and are enriched in biological pathways related to synaptic transmission 208.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [208] Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019;22:343–52. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“D2R activation leads to long-lasting NMDAR hypofunction, resulting in the profound disruption of functional connectivity between hippocampus and PFC 167.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [167] Banks PJ, Burroughs AC, Barker GR, Brown JT, Warburton EC, Bashir ZI. Disruption of hippocampal-prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission. Proc Natl Acad Sci USA. 2015;112:11096–101. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A systematic review of literatures reported the increased expression of 5-HT1A and the reduced expression of 5-HT2A receptors in PFC of SZ patients 193.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [193] Selvaraj S, Arnone D, Cappai A, Howes O. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev. 2014;45:233–45. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The PFC has also emerged as a hub for MDD treatment, as repeated transcranial magnetic stimulation (rTMS) therapy targeting the left PFC appears effective in mitigating depression symptoms 207.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [207] Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder. Brain Stimul. 2016;9:336–46. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a mouse model carrying a genetic risk factor for neuropsychiatric disorders, adolescent isolation stress induces DNA hypermethylation of the tyrosine hydroxylase (TH) gene in mesocortical dopaminergic neurons, causing the reduced TH expression and cortical dopamine release, leading to SZ-associated behavioral abnormalities 187.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [187] Niwa M, Jaaro-Peled H, Tankou S, Seshadri S, Hikida T, Matsumoto Y, et al. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science. 2013;339:335–9. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“D1R activation in PFC facilitates the maintenance of long-term potentiation (LTP) of glutamatergic transmission, as well as the induction of long-term depression (LTD) of glutamatergic transmission, indicating its bidirectional modulation of synaptic plasticity in mPFC 189.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Schizophrenia
What the sources say
- Not checked yetcites [189] Huang YY, Simpson E, Kellendonk C, Kandel ER. Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci USA. 2004;101:3236–41. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these studies suggest that in MDD patients, the PFC is characterized by diminished expression of glutamatergic and GABAergic receptors, accompanied by a reduction in dendritic spine density.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The ketamine-induced elevation in PFC glutamate release promotes AMPA receptor activation, which is necessary for ketamine’s antidepressant effects; pre-administration of the AMPAR receptor antagonist NBQX prevents ketamine’s antidepressant-like behavioral effects in mice 226.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [226] Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–52. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Twenty genes are found to be differentially methylated in PFC of MDD patients from a genome-wide methylation analysis, including hypermethylation of Grin2a 232.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [232] Kaut O, Schmitt I, Hofmann A, Hoffmann P, Schlaepfer TE, Wullner U, et al. Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression. Eur Arch Psychiatry Clin Neurosci. 2015;265:331–41. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In rodents, low doses of ketamine have been shown to drive the increased glutamate release 222 and glutamate cycling 223 in PFC.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [222] Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7. source
- Not checked yetcites [223] Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–6. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ketamine treatment thus enacts its therapeutic effects by transiently promoting glutamate release in PFC to activate AMPA receptors, which in turn activates the downstream mTOR signaling pathway and promotes BDNF expression, leading to synaptogenesis and elevated glutamatergic transmission (Fig. 4B).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“and inhibiting H3K4-specific methyltransferases, including MLL1-4 (also named as KMT2A-D) and SETD1a/b, leads to the substantial recovery of glutamatergic synaptic function in PFC pyramidal neurons, and the significant improvement of memory-related behaviors in mutant Tau transgenic mice 260.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [260] Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6:eabc8096. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“From aging monkey studies, it is found that PFC is particularly vulnerable to calcium dysregulation and tau phosphorylation 240.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [240] Arnsten AFT, Datta D, Leslie S, Yang ST, Wang M, Nairn AC. Alzheimer’s-like pathology in aging rhesus macaques: unique opportunity to study the etiology and treatment of Alzheimer’s disease. Proc Natl Acad Sci USA. 2019;116:26230–8. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Elevated DNA methylation is observed in PFC of rats subjected to learned helplessness stress, which is reversed by antidepressant imipramine treatment 235.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Depression
What the sources say
- Not checked yetcites [235] Sales AJ, Joca SRL. Antidepressant administration modulates stress-induced DNA methylation and DNA methyltransferase expression in rat prefrontal cortex and hippocampus. Behavioural Brain Res. 2018;343:8–15. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Guanfacine, a specific α2-AR antagonist, has been used to treat cognitive disorders linked to PFC dysfunction 251.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [251] Arnsten AF, Wang M. Targeting prefrontal cortical systems for drug development: potential therapies for cognitive disorders. Annu Rev Pharm Toxicol. 2016;56:339–60. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Treatment of AD models with specific EHMT1/2 inhibitors reverses the increased H3K9me2 enrichment at genes involved in neuronal signaling (e.g. Grin2b encoding NR2B subunit and Gria2 encoding GluR2 subunit), restores glutamate receptor expression and excitatory synaptic function in PFC, and rescues the impaired recognition memory, working memory, and spatial memory 256 (Fig. 5).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [256] Zheng Y, Liu A, Wang ZJ, Cao Q, Wang W, Lin L, et al. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain. 2019;142:787–807. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“and the decreased expression of these synaptic genes in later Braak stages, suggesting a reduction in synaptic activity that coincides with AD neuropathology and cognitive impairment 252.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [252] Bossers K, Wirz KT, Meerhoff GF, Essing AH, van Dongen JW, Houba P, et al. Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain. 2010;133:3699–723. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In aged monkeys with naturally occurring cholinergic depletion, low-dose muscarinic M1R stimulation enhances delay firing in dorsolateral PFC neurons and improves working memory via a mechanism involving KCNQ channels 248.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [248] Galvin VC, Yang ST, Paspalas CD, Yang Y, Jin LE, Datta D, et al. Muscarinic M1 receptors modulate working memory performance and activity via KCNQ potassium channels in the primate prefrontal cortex. Neuron. 2020;106:649–61.e644. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Novel epigenetic mechanism-based strategies have been proposed as potential avenues of therapeutic intervention for mental diseases linked to PFC dysfunction.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Concluding Remarks
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“A short treatment with the specific SGK1 inhibitor results in the significant reduction of hyper-phosphorylated tau (a pathological hallmark of AD) and the recovery of synaptic receptor expression and glutamatergic transmission in PFC, as well as the restoration of recognition and spatial memories, in mutant Tau transgenic mice 260 (Fig. 5).”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Alzheimer’s Disease
What the sources say
- Not checked yetcites [260] Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6:eabc8096. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies in animal models have revealed critical neural circuits, biological pathways, and molecular players that converge to control the excitatory and inhibitory signals in PFC networks.”
§ Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications > Concluding Remarks
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper relies on this without support.
PFC is the last portion of the brain to fully develop.
“PFC is the last portion of the brain to fully develop.”
The paper relies on this without support.
Human PFC is delineated into two functionally, morphologically, and evolutionarily different regions: ventromedial PFC and lateral PFC.
“PFC of humans is delineated into two functionally, morphologically, and evolutionarily different regions: ventromedial PFC and lateral PFC.”
The paper relies on this without support.
Most clinically effective antipsychotic drugs, antidepressants and anxiolytics exert potent effects on the serotonin system.
“Most clinically effective antipsychotic drugs, antidepressants and anxiolytics all exert potent effects on the serotonin system.”
The paper relies on this without support.
Autism is a prevalent neurodevelopmental disorder characterized by core symptoms like social deficits and stereotypic behaviors.
“Autism is a prevalent neurodevelopmental disorder characterized by core symptoms like social deficits and stereotypic behaviors.”
The paper relies on this without support.
Many of the high-level executive functions controlled by PFC are impaired in autism.
“Many of the high-level executive functions controlled by PFC are impaired in autism.”
The paper relies on this without support.
Neuropeptide Y is a stress modulatory transmitter associated with PTSD.
“Neuropeptide Y (NPY), a stress modulatory transmitter, has been associated with PTSD.”
The paper relies on this without support.
PFC is one of the first regions affected in clinical Alzheimer's disease.
“PFC is one of the first regions to be affected in clinical AD, which may explain the early occurrence of the impairment of PFC-mediated cognitive processes, such as working memory and attention.”
The paper relies on this without support.
Aging is the leading risk factor for developing Alzheimer's disease.
“Aging is the leading risk factor for developing AD, so many studies have focused on revealing neurobiological changes that affect synaptic integrity with aging and why aged brain is vulnerable to AD.”
The paper relies on this without support.
Findings from animal models of neuropsychiatric and neurodegenerative disorders can be generalized to human patients.
“Studies in animal models have revealed critical neural circuits, biological pathways, and molecular players that converge to control the excitatory and inhibitory signals in PFC networks.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These traits are partially rooted in neurobiological variation, particularly dysfunctional dopaminergic signaling in the striatum and impaired prefrontal cortical regulation of subcortical emotional and motivational responses.20”
From Beyond Stigma–Integrating Neurobiology, Genetics, and Awareness Integration Theory in Addiction Recovery (2026) · cites this paper as [20]
Experimental — accuracy not yet measured
Citations
Cites
Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369
Diamond, A. (2013) · Annual Review of Psychology · doi:10.1146/annurev-psych-113011-143750 · Cited by 13,268
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881 · cited 2×
“Decreased levels of mTORC are found in the PFC of humans with the major depressive disorder [112], and the fast-acting antidepressant ketamine increases mTORC signaling in rat PFC [113].”
BackgroundSynaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · cited 1×
“Another identified high-risk factor for autism is the Cullin 3 (Cul3) gene [141], which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation [149].”
Cellular basis of working memory
Goldman-Rakic, P. S. (1995) · Neuron · doi:10.1016/0896-6273(95)90304-6 · Cited by 2,663 · cited 2×
“The key fi ndings are that in a delayed reaching task, some primate dorsolateral PFC neurons exhibit the increased fi ring during the delay period when response-related information needs to be held in mind to guide the subsequent execution of correct responses [4, 5].”
BackgroundOngur, D. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.3.206 · Cited by 2,627 · cited 1×
“Based on anatomical, functional, and connectivity homologies, it is thought that rodent PFC is composed of three cytoarchitecturally de fi ned parts: the prelimbic (PL), infralimbic (IL), and anterior cingulate cortex (ACC) [11, 12].”
BackgroundSingle-cell transcriptomic analysis of Alzheimer’s disease
Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J. Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al. (2019) · Nature · doi:10.1038/s41586-019-1195-2 · Cited by 2,568
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0326-7 · Cited by 2,565
Cited by
Sorted by citations
Wang, X., Wang, B., Wu, C., Wang, J., & Sun, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031819 · Cited by 305
Wang, Z., Shwani, T., Liu, J., Zhong, P., Yang, F., Schatz, K. C., Zhang, F., Pralle, A., & Yan, Z. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01574-y · Cited by 66
“To find out whether the diminished sociability in SI females is driven by the neuronal activity changes in PFC, a key region involved in social behaviors [8, 14, 41, 42], we performed in vivo calcium imaging of behaving animals.”
BackgroundSelf-citationPostsynaptic autism spectrum disorder genes and synaptic dysfunction
Bonsi, P., Jaco, A. D., Fasano, L., & Gubellini, P. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105564 · Cited by 68
Human forebrain organoids reveal connections between valproic acid exposure and autism risk
Meng, Q., Zhang, W., Wang, X., Jiao, C., Xu, S., Liu, C., Tang, B., & Chen, C. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01898-x · Cited by 65
Qin, L., Williams, J. B., Tan, T., Liu, T., Cao, Q., Ma, K., & Yan, Z. (2021) · Nature Communications · doi:10.1038/s41467-021-26972-8 · Cited by 64
Self-citation
Metadata
- Authors
- Yan, Z., & Rein, B.
- Affiliations
- University at Buffalo, State University of New York (US)
- Corresponding author
- Yan, Zhen
- Venue
- Molecular Psychiatry
- Published
- 2021-04-19
- Volume
- 27
- Issue
- 1
- Pages
- 445-465
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC8523584
- OpenAlex
- W3154550139
- Cited by
- 300
- References
- 278
- Citations by year
- 2026: 54 · 2025: 78 · 2024: 60 · 2023: 56 · 2022: 39 · 2021: 13
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH108842)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG056060)
- U.S. Department of Health & Human Services | National Institutes of Health (AG064656, AG067597)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- prefrontal cortex, synaptic transmission, GABAergic interneurons, dopamine, serotonin, stress hormones, neuropeptides, autism spectrum disorder, schizophrenia, depression, Alzheimer's disease, social dysfunction, memory loss, epigenetic therapy, neuropsychiatric disorders, neurodevelopmental disorders, neurodegenerative diseases
- MeSH terms
- Humans, Interneurons, Memory, Short-Term, Synaptic Transmission, Neurons, Prefrontal Cortex
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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