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Cited by 300Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorGenetics and Neurodevelopmental Disorders

Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications

Open access
Yan, Zhen, Rein, Benjamin·2022·Molecular Psychiatry
DOI 10.1038/s41380-021-01092-3PMC PMC8523584
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Abstract

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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Crossref · 10.1038/s41380-021-01092-3

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  • Premisecitation

    In a delayed reaching task, some primate dorsolateral PFC neurons exhibit increased firing during the delay period when response-related information needs to be held in mind.

    “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.”
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    • cites [4] Fuster JM, Alexander GE. Neuron activity related to short-term memory. Science. 1971;173:652–4. source

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    • cites [5] Goldman-Rakic PS. Cellular basis of working memory. Neuron. 1995;14:477–85. source

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  • Premisecitation

    A frontal cortical area in the rat exhibits increased firing during the delay period in the absence of sensory stimulus, as in primate PFC.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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  • Premisecitation

    A spatiotemporal dynamic network originating in PFC and ventral striatum, relaying through amygdala and VTA, and converging in vHIP encodes depression vulnerability in mice subjected to social defeat stress.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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  • Premisecitation

    Dorsomedial PFC exerts top-down control of motor cortex ensembles to inhibit inappropriate responses during a delayed-response task.

    “Dorsomedial PFC exerts the top-down control of motor cortex ensembles to inhibit inappropriate responses during a delayed-response task 18.”
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    • cites [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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  • Premisecitation

    The BLA-to-PL circuit is critical in governing selection of behavioral responses amid conflicting cues of reward and punishment.

    “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.”
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    • cites [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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    Premisecitation

    Neuroimaging studies implicate human PFC in higher-order cognitive processing including working memory and sustained attention.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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    Premisecitation

    PFC FS interneurons (PV+) contact perisomatic domains of pyramidal neurons, while non-FS interneurons (SST+) contact peridendritic domains, enabling PV+ and SST+ interneurons to specialize in control of output and input of principal neurons.

    “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.”
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    • cites [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

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    Premisecitation

    In monkey PFC neurons, the rapid phase of synaptogenesis reaches a plateau at 2 months old, and synaptic density remains consistently high from early adolescence through puberty (2 months to 3 years).

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;4:78–96. source

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    Premisecitation

    Thalamic input amplifies PFC connectivity, sustaining attentional control and enabling sensory selection in divided attention.

    “Thalamic input amplifies PFC connectivity, sustaining attentional control 24 and enabling sensory selection in divided attention 25.”
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    • cites [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

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    • cites [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

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    Premisecitation

    Rodent PFC is composed of three cytoarchitecturally defined parts: prelimbic, infralimbic, and anterior cingulate cortex.

    “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.”
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    • cites [11] Uylings HB, Groenewegen HJ, Kolb B. Do rats have a prefrontal cortex? Behavioural Brain Res. 2003;146:3–17. source

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    • cites [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

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    Premisecitation

    Social defeat weakens functional connectivity between mPFC and a brainstem area, and selective inhibition of this pathway recaptures behavioral effects of social defeat.

    “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.”
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    • cites [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

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    Premisecitation

    Deep layer PFC pyramidal neurons project to mediodorsal thalamus, lateral hypothalamus, ventral and dorsal striatum, and basolateral amygdala.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    PV+ interneurons 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Stimulation of PFC-to-NAc neurons promotes conditioned reward-seeking behaviour, while activation of PFC-to-thalamic neurons suppresses both acquisition and expression of conditioned reward seeking.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Direct hippocampal-to-prefrontal afferents in mice are critical for encoding spatial cues during working memory, and successful encoding of task-related information is mediated by gamma-frequency synchrony between hippocampus and PFC.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Interpretationreasoning

    Optimal levels of dopamine are essential for PFC function, while excessive dopamine stimulation could be detrimental.

    “It suggests that optimal levels of dopamine are essential for PFC function, while excessive dopamine stimulation could be detrimental.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Dampening thalamic activity causes reductions of GABA signaling in mPFC and abnormalities in cognition and social interaction, ameliorated by activating mPFC PV+ interneurons.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Dopamine has no effect on excitatory transmission from pyramidal neurons to FS interneurons, but increases the excitability of FS interneurons.

    “Dopamine has no effect on excitatory transmission from pyramidal neurons to FS interneurons, but increases the excitability of FS interneurons 52.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    In mice performing a reward foraging task, SST+ interneurons in ACC selectively respond at reward approach, whereas PV+ interneurons respond at reward leaving.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Interpretationcitation

    SST+ interneurons are uniquely involved in facilitating hippocampal-prefrontal synchrony and prefrontal spatial encoding.

    “suggesting that SST+ interneurons are uniquely involved in facilitating hippocampal-prefrontal synchrony and prefrontal spatial encoding.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Blocking dopamine receptor activation in PFC shortens VTA excitation of PFC PV+ interneurons and prolongs VTA excitation of PFC principal neurons.

    “Blocking dopamine receptor activation in PFC shortens the VTA excitation of PFC PV+ interneurons and prolongs the VTA excitation of PFC principal neurons”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    PV interneurons show weak target-dependent delay-period activity and are strongly inhibited by reward; SST+ interneurons show strong target-dependent delay-period activity, and only a subtype is inhibited by reward.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Optogenetic stimulation of VTA neurons reveals a marked and prolonged enhancement of excitability of PFC PV+ interneurons and a modest and short-lived enhancement of excitability of PFC principal neurons.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Inhibition of mPFC SST+ interneurons abolishes affective state discrimination, and increased synchronous activity of PFC SST+ interneurons is associated with this social cognitive function.

    “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”
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    • cites [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

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    Premisecitation

    In a PFC-dependent sensory discrimination task, PV+ interneurons respond to sensory cues, motor action, and trial outcomes, while SST+ and VIP+ interneurons respond more selectively to motor action or trial outcomes.

    “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.”
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    • cites [37] Pinto L, Dan Y. Cell-type-specific activity in prefrontal cortex during goal-directed behavior. Neuron. 2015;87:437–50. source

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    Premisecitation

    The majority of dopamine synapses in all PFC layers are on pyramidal neurons, but a significant fraction are on GABAergic interneurons.

    “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.”
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    • cites [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

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    Premisecitation

    Inhibiting PFC pyramidal neurons by activating SST+ or PV+ interneurons during the delay impairs working memory performance, while activating VIP+ interneurons improves memory retention.

    “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”
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    • cites [40] Kamigaki T, Dan Y. Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior. Nat Neurosci. 2017;20:854–63. source

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    Premisecitation

    Stimulation of α2A-ARs enhances spatially-tuned, delay-related firing of PFC neurons and strengthens working memory networks through inhibition of cAMP and closing HCN channels.

    “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.”
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    • cites [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

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    Premisecitation

    High levels of D1R activation of cAMP signaling reduces PFC neuronal firing and impairs working memory via opening of HCN channels at excitatory synapses.

    “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.”
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    • cites [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

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    Premisecitation

    Optogenetically inhibiting PFC SST+, but not PV+, interneurons decreases long-range synchrony between hippocampus and PFC and impairs working memory accuracy.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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    Premisecitation

    Dopamine depresses inhibitory transmission between FS interneurons and pyramidal neurons, but enhances inhibition between non-FS interneurons and pyramidal cells.

    “DA depressed inhibitory transmission between FS interneurons and pyramidal neurons, but enhanced inhibition between non-FS interneurons and pyramidal cells 28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Endogenous norepinephrine acting on α1-ARs increases firing of some PFC pyramidal neurons via presynaptic excitation of glutamate release under basal conditions, but high α1-AR stimulation suppresses PFC neuronal firing through opening of K+ channels on spines.

    “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.”
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    • cites [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

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    Premisecitation

    Reduced catecholamine transmission has been linked to ADHD, while overamplified noradrenergic transmission is associated with PTSD.

    “Reduced catecholamine transmission has been linked to ADHD, while overamplified noradrenergic transmission is associated with PTSD 46.”
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    • cites [46] Arnsten AF. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011;69:e89–99. source

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    Premisecitation

    Reduced SGK expression is found in postmortem brains of PTSD patients, and inhibition of SGK in rat PFC produces helplessness- and anhedonia-like phenotypes.

    “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.”
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    • cites [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

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    Premisecitation

    VGF in PFC regulates susceptibility to stress and antidepressant response to ketamine, and infusion of VGF C-terminal peptide TLQP-62 to PFC produces sustained antidepressant responses.

    “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.”
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    • cites [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

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    Premisecitation

    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.

    “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”
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    • cites [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

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    Premisecitation

    5-HT1A receptors in PFC pyramidal neurons suppress NMDAR function by disrupting microtubule/kinesin-based dendritic transport of NMDA receptors, and this effect is opposed by 5-HT2A/C signaling.

    “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.”
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    • cites [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

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    • cites [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

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    Premisecitation

    NPY in IL cortex, acting on NPY Y1 receptors, increases inhibitory synaptic transmission onto IL projection neurons and dampens their excitability, impairing fear extinction memory.

    “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.”
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    • cites [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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    Premisecitation

    REDD1 shows elevated expression in PFC of animals exposed to chronic unpredictable stress and PFC of post-partum depressed humans.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Decreased levels of mTORC are found in PFC of humans with major depressive disorder, and ketamine increases mTORC signaling in rat PFC.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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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    • cites [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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    Premisecitation

    Acute footshock stress increases spine density and induces dendritic remodeling in medial PFC, partially blocked by chronic desipramine.

    “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.”
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    • cites [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

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    • cites [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.

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    Premisecitation

    Chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampus-PFC connection, and repeated social stress during mid-adolescence decreases synaptic activity and intrinsic excitability of mPFC neurons.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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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    Premisecitation

    Reduced levels of VGF have been found in PFC of MDD patients and PFC of chronically stressed mice.

    “Reduced levels of VGF have been found in PFC of MDD patients and PFC of chronically stressed mice 116.”
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    • cites [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

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    Premisecitation

    At thalamocortical synapses, 5-HT2A activation enhances NMDA transmission, gates induction of NMDAR-mediated temporal plasticity, and facilitates associated cognitive functions.

    “At thalamocortical synapses, 5-HT2A activation enhances NMDA transmission, gates the induction of NMDAR-mediated temporal plasticity, and facilitates associated cognitive functions 91.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Chronic stress produces impaired dendritic branching, atrophy and spine loss in PFC pyramidal neurons, reversed after 3-week cessation of stress.

    “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.”
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    • cites [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

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    • cites [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

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    • cites [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

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    Premisecitation

    5-HT2 receptors inhibit GABAAR-mediated currents in PFC pyramidal neurons through phosphorylation of GABAA receptors by anchored PKC, while 5-HT4 receptors modulate GABAergic signaling bi-directionally depending on basal PKA activation levels.

    “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.”
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    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

    Transcriptomic meta-analyses across major neuropsychiatric disorders found shared transcriptional dysregulation including a gradient of synaptic gene down-regulation and astroglial gene up-regulation in ASD, SZ and BD (ASD > SZ = BD), and dysregulation of HPA-axis and hormonal signaling in MDD.

    “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”
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    • cites [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

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    Premisecitation

    Chemogenetic activation of PFC pyramidal neurons in Shank3-deficient mice restores social preference behaviors and elevates glutamatergic synaptic function.

    “Chemogenetic activation of PFC pyramidal neurons in Shank3-deficient mice also restores social preference behaviors and elevates glutamatergic synaptic function 129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Inhibition of EHMT1/2 rescues social deficits and restores PFC NMDAR function in Shank3-deficient mice via restoring expression of plasticity gene Arc.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Chemogenetic activation of PFC pyramidal neurons ameliorates cognitive and social impairments and restores NMDAR function in 16p11+/− mice.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Systemic administration of class I HDAC inhibitor romidepsin or MS-275 leads to robust and persistent alleviation of social deficits and restoration of actin regulators and NMDAR function in PFC.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

    Reduced synaptic plasticity in hippocampus-mPFC pathway and impaired social recognition memory and attention in Shank3-deficient rats are attenuated by oxytocin treatment.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Loss of Cul3 in forebrain or PFC leads to social deficits and NMDAR hypofunction.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Inhibition or knockdown of Smyd3 ameliorates social deficits and restores PFC NMDAR function in forebrain Cul3-deficient mice.

    “Inhibition or knockdown of Smyd3 ameliorates social deficits and restores PFC NMDAR function in forebrain Cul3-deficient mice 147.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    In PFC of Shank3-deficient mice, loss of histone acetylation and upregulation of HDAC2 have been identified.

    “In PFC of Shank3-deficient mice, the loss of histone acetylation and upregulation of HDAC2 have been identified 145.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Inhibiting cofilin or activating Rac1 rescues social deficits and NMDAR hypofunction in Shank3-deficient mice.

    “Inhibiting cofilin or activating Rac1 rescues the social deficits and NMDAR hypofunction in Shank3-deficient mice 127”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    Restoring Npas4 expression ameliorates social and cognitive deficits, GABAergic synaptic impairment, and neuronal hyperexcitability in 16p11dp/+ mice.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

    16p11.2 duplication mouse model exhibits deficient GABAergic synaptic transmission and elevated excitability in PFC pyramidal neurons.

    “On the other hand, a 16p11.2 duplication mouse model, 16p11dp/+, exhibits deficient GABAergic synaptic transmission and elevated excitability in PFC pyramidal neurons 134.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    In PFC pyramidal neurons of Shank3-deficient mice, NMDAR function and synaptic distribution are significantly diminished.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Premisecitation

    SZ has been linked to 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.

    “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.”
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    • cites [151] Selemon LD, Zecevic N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry. 2015;5:e623. source

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  • May combine two claims.

    Premisecitation

    Loss of Cul3 in striatum leads to stereotypic behaviors and cell type-specific alteration of neuronal excitability in striatal circuits.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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    Premisecitation

    Reduced PV expression at individual cellular level and within presynaptic boutons of PV+ basket cells in SZ patients.

    “the reduced PV expression is reported both at the individual cellular level 181 and specifically within presynaptic boutons of PV+ basket cells 182.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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    Premisecitation

    In rats treated with NMDAR antagonists, PFC neurons display elevated and irregular spiking activity and reduced coordinated burst firing.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    NMDAR-mediated connectivity between PFC and hippocampus is impaired in SZ, suggested as mechanism underlying working memory deficits.

    “NMDAR-mediated connectivity between PFC and hippocampus is impaired in SZ, which is suggested as a mechanism underlying working memory deficits 167.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Decreased GAD67 expression and reduced gamma oscillations in PFC of SZ patients.

    “including the decreased GAD67 expression and reduced gamma oscillations, suggesting deficient GABA synthesis and GABAergic synaptic transmission, respectively 180.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    Proteomic analysis of SZ DLPFC samples identified 15 differentially expressed proteins, 7 of which were synaptic.

    “Proteomic analysis of SZ DLPFC samples identified 15 differentially expressed proteins, 7 of which were synaptic 164.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    There is strong support for NMDA hypofunction in SZ, as treatment with NMDAR antagonists can induce SZ-like symptoms in both human subjects and animals.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [165] Nakazawa K, Jeevakumar V, Nakao K. Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia. npj Schizophr. 2017;3:7. source

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    • cites [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

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  • May combine two claims.

    Premisecitation

    Blocking NMDARs with MK-801 injection leads to impairment of mPFC-dependent cognitive flexibility and hippocampus-mPFC pathway-dependent spatial working memory.

    “Blocking NMDARs with MK-801 injection leads to the impairment of mPFC-dependent cognitive flexibility and hippocampus-mPFC pathway-dependent spatial working memory 168.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Interpretationnone given

    MDD is associated with aberrant synaptic transmission in PFC, affecting both GABA and glutamate systems.

    “MDD is associated with aberrant synaptic transmission in PFC, affecting both GABA and glutamate systems (Fig. 4B).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Computational models predict that imbalance of D1R/D2R activation in PFC may underlie associated cognitive, positive and negative symptoms of SZ.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation

    D2R activation leads to long-lasting NMDAR hypofunction, resulting in profound disruption of functional connectivity between hippocampus and PFC.

    “D2R activation leads to long-lasting NMDAR hypofunction, resulting in the profound disruption of functional connectivity between hippocampus and PFC 167.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systematic review reported increased expression of 5-HT1A and reduced expression of 5-HT2A receptors in PFC of SZ patients.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    PFC has emerged as a hub for MDD treatment, as rTMS targeting left PFC appears effective in mitigating depression symptoms.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    In a mouse model carrying a genetic risk factor for neuropsychiatric disorders, adolescent isolation stress induces DNA hypermethylation of TH gene in mesocortical dopaminergic neurons, causing reduced TH expression and cortical dopamine release, leading to SZ-associated behavioral abnormalities.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    D1R activation in PFC facilitates maintenance of LTP of glutamatergic transmission and induction of LTD of glutamatergic transmission.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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  • May combine two claims.

    Interpretationcitation

    In MDD patients, PFC is characterized by diminished expression of glutamatergic and GABAergic receptors, accompanied by reduction in dendritic spine density.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ketamine-induced elevation in PFC glutamate release promotes AMPA receptor activation, which is necessary for ketamine's antidepressant effects.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Twenty genes are differentially methylated in PFC of MDD patients from genome-wide methylation analysis, including hypermethylation of Grin2a.

    “Twenty genes are found to be differentially methylated in PFC of MDD patients from a genome-wide methylation analysis, including hypermethylation of Grin2a 232.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, low doses of ketamine drive increased glutamate release and glutamate cycling in PFC.

    “In rodents, low doses of ketamine have been shown to drive the increased glutamate release 222 and glutamate cycling 223 in PFC.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Ketamine treatment enacts therapeutic effects by transiently promoting glutamate release in PFC to activate AMPA receptors, which in turn activates downstream mTOR signaling pathway and promotes BDNF expression, leading to synaptogenesis and elevated glutamatergic transmission.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Inhibiting H3K4-specific methyltransferases leads to substantial recovery of glutamatergic synaptic function in PFC pyramidal neurons and significant improvement of memory-related behaviors in mutant Tau transgenic mice.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PFC is particularly vulnerable to calcium dysregulation and tau phosphorylation.

    “From aging monkey studies, it is found that PFC is particularly vulnerable to calcium dysregulation and tau phosphorylation 240.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated DNA methylation is observed in PFC of rats subjected to learned helplessness stress, which is reversed by antidepressant imipramine treatment.

    “Elevated DNA methylation is observed in PFC of rats subjected to learned helplessness stress, which is reversed by antidepressant imipramine treatment 235.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Guanfacine, a specific α2-AR antagonist, has been used to treat cognitive disorders linked to PFC dysfunction.

    “Guanfacine, a specific α2-AR antagonist, has been used to treat cognitive disorders linked to PFC dysfunction 251.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of AD models with specific EHMT1/2 inhibitors reverses increased H3K9me2 enrichment at genes involved in neuronal signaling, restores glutamate receptor expression and excitatory synaptic function in PFC, and rescues impaired recognition memory, working memory, and spatial memory.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased expression of these synaptic genes in later Braak stages, suggesting reduction in synaptic activity that coincides with AD neuropathology and cognitive impairment.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 mechanism involving KCNQ channels.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Novel epigenetic mechanism-based strategies have been proposed as potential avenues of therapeutic intervention for mental diseases linked to PFC dysfunction.

    “Novel epigenetic mechanism-based strategies have been proposed as potential avenues of therapeutic intervention for mental diseases linked to PFC dysfunction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Short treatment with specific SGK1 inhibitor results in significant reduction of hyper-phosphorylated tau and recovery of synaptic receptor expression and glutamatergic transmission in PFC, as well as restoration of recognition and spatial memories, in mutant Tau transgenic mice.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Studies in animal models have revealed critical neural circuits, biological pathways, and molecular players that converge to control excitatory and inhibitory signals in PFC networks.

    “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.”
    Quote in the paperNot a substantial claim
86 of 86

  • 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.”
9 of 9

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?

  • 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.

    “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]

    The PFC network organization section (page unavailable) describes prefrontal projections that regulate reward seeking, and the Schizophrenia section reports that striatal D2-receptor overexpression in mice can disrupt inhibitory input to the PFC. The Dopamine section also links a dopamine-receptor variant to novelty seeking. These passages support parts of the proposed neurobiological account, but they do not establish that the unspecified traits arise from dysfunctional striatal dopamine signaling together with impaired prefrontal regulation of subcortical emotional and motivational responses. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

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10 of the 278 references couldn’t be matched to a known paper.

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Related

Authors
Yan, Z., & Rein, B.
Affiliations
University at Buffalo, State University of New York (US)
Corresponding author
Yan, Zhen
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-04-19
Volume
27
Issue
1
Pages
445-465
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-021-01092-3
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
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

About these checks

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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