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

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.”

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

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.”

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

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.”

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

In the paper

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

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

What the sources say

• Not checked yetcites [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

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.”

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

In the paper

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

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.”

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

In the paper

“Dopamine has no effect on excitatory transmission from pyramidal neurons to FS interneurons, but increases the excitability of FS interneurons 52.”

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

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.”

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

In the paper

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

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

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”

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

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.”

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

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.”

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

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”

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

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.”

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

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.”

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

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”

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

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.”

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

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.”

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

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”

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

In the paper

“DA depressed inhibitory transmission between FS interneurons and pyramidal neurons, but enhanced inhibition between non-FS interneurons and pyramidal cells 28.”

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

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.”

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

In the paper

“Reduced catecholamine transmission has been linked to ADHD, while overamplified noradrenergic transmission is associated with PTSD 46.”

What the sources say

• Not checked yetcites [46] Arnsten AF. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011;69:e89–99. source

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.”

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

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.”

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

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”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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.

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.”

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.

In the paper

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

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

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.”

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

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.”

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 [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

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.”

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

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”

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

In the paper

“Chemogenetic activation of PFC pyramidal neurons in Shank3-deficient mice also restores social preference behaviors and elevates glutamatergic synaptic function 129.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

In the paper

“Inhibition or knockdown of Smyd3 ameliorates social deficits and restores PFC NMDAR function in forebrain Cul3-deficient mice 147.”

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

In the paper

“In PFC of Shank3-deficient mice, the loss of histone acetylation and upregulation of HDAC2 have been identified 145.”

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

In the paper

“Inhibiting cofilin or activating Rac1 rescues the social deficits and NMDAR hypofunction in Shank3-deficient mice 127”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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

In the paper

“including the decreased GAD67 expression and reduced gamma oscillations, suggesting deficient GABA synthesis and GABAergic synaptic transmission, respectively 180.”

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

In the paper

“Proteomic analysis of SZ DLPFC samples identified 15 differentially expressed proteins, 7 of which were synaptic 164.”

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

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.”

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

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.”

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

In the paper

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

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.”

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

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.”

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

In the paper

“D2R activation leads to long-lasting NMDAR hypofunction, resulting in the profound disruption of functional connectivity between hippocampus and PFC 167.”

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

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.”

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

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.”

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

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.”

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

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.”

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

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.”

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.”

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

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.”

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

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.”

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

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).”

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.”

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

In the paper

“From aging monkey studies, it is found that PFC is particularly vulnerable to calcium dysregulation and tau phosphorylation 240.”

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

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.”

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

In the paper

“Guanfacine, a specific α2-AR antagonist, has been used to treat cognitive disorders linked to PFC dysfunction 251.”

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

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).”

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

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.”

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

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.”

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

In the paper

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

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).”

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

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.”