Mechanisms of Synaptic Transmission Dysregulation in the Prefrontal Cortex: Pathophysiological Implications

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2021 Apr 20

PMID 33875802

Citations 88

Authors

Zhen Yan

Benjamin Rein

Affiliations

Soon will be listed here.

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.

Citing Articles

Increased individual variability in functional connectivity of the default mode network and its genetic correlates in major depressive disorder.

Yao C, Wang P, Xiao Y, Zheng Y, Pu J, Miao Y Sci Rep. 2025; 15(1):8853.

PMID: 40087380 DOI: 10.1038/s41598-025-92849-1.

Dose-dependent developmental fluoride exposure leads to neurotoxicity and impairs excitatory synapse development.

Qiu W, Wang X, Zhang S, Zhang Z, Zhang K, Shao Z Arch Toxicol. 2025; .

PMID: 40085203 DOI: 10.1007/s00204-025-04003-5.

Somatostatin-expressing interneurons of prefrontal cortex modulate social deficits in the Magel2 mouse model of autism.

Wang X, Chen M, Mei D, Shi S, Guo J, Gao C Mol Autism. 2025; 16(1):18.

PMID: 40069835 PMC: 11895276. DOI: 10.1186/s13229-025-00653-5.

In-depth and high-throughput spatial proteomics for whole-tissue slice profiling by deep learning-facilitated sparse sampling strategy.

Qin R, Ma J, He F, Qin W Cell Discov. 2025; 11(1):21.

PMID: 40064869 PMC: 11894098. DOI: 10.1038/s41421-024-00764-y.

Amphetamine in Adolescence Induces a Sex-Specific Mesolimbic Dopamine Phenotype in the Adult Prefrontal Cortex.

Hernandez G, Zhao J, Niu Z, MacGowan D, Capolicchio T, Song A bioRxiv. 2025; .

PMID: 40060609 PMC: 11888448. DOI: 10.1101/2025.02.26.640363.

References

Bourgeois J, Goldman-Rakic P, Rakic P . Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994; 4(1):78-96. DOI: 10.1093/cercor/4.1.78. View

Diamond A . Executive functions. Annu Rev Psychol. 2012; 64:135-68. PMC: 4084861. DOI: 10.1146/annurev-psych-113011-143750. View

Stokes M . 'Activity-silent' working memory in prefrontal cortex: a dynamic coding framework. Trends Cogn Sci. 2015; 19(7):394-405. PMC: 4509720. DOI: 10.1016/j.tics.2015.05.004. View

Fuster J, Alexander G . Neuron activity related to short-term memory. Science. 1971; 173(3997):652-4. DOI: 10.1126/science.173.3997.652. View

Goldman-Rakic P . Cellular basis of working memory. Neuron. 1995; 14(3):477-85. DOI: 10.1016/0896-6273(95)90304-6. View

Wang Y, Markram H, Goodman P, Berger T, Ma J, Goldman-Rakic P . Heterogeneity in the pyramidal network of the medial prefrontal cortex. Nat Neurosci. 2006; 9(4):534-42. DOI: 10.1038/nn1670. View

Compte A, Brunel N, Goldman-Rakic P, Wang X . Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Cereb Cortex. 2000; 10(9):910-23. DOI: 10.1093/cercor/10.9.910. View

Wang M, Yang Y, Wang C, Gamo N, Jin L, Mazer J . NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron. 2013; 77(4):736-49. PMC: 3584418. DOI: 10.1016/j.neuron.2012.12.032. View

McCarthy G, Blamire A, Puce A, Nobre A, Bloch G, Hyder F . Functional magnetic resonance imaging of human prefrontal cortex activation during a spatial working memory task. Proc Natl Acad Sci U S A. 1994; 91(18):8690-4. PMC: 44672. DOI: 10.1073/pnas.91.18.8690. View

10.

Pardo J, Fox P, Raichle M . Localization of a human system for sustained attention by positron emission tomography. Nature. 1991; 349(6304):61-4. DOI: 10.1038/349061a0. View

11.

Ongur D, Price J . The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000; 10(3):206-19. DOI: 10.1093/cercor/10.3.206. View

12.

Erlich J, Bialek M, Brody C . A cortical substrate for memory-guided orienting in the rat. Neuron. 2011; 72(2):330-43. PMC: 3212026. DOI: 10.1016/j.neuron.2011.07.010. View

13.

Baeg E, Kim Y, Huh K, Mook-Jung I, Kim H, Jung M . Dynamics of population code for working memory in the prefrontal cortex. Neuron. 2003; 40(1):177-88. DOI: 10.1016/s0896-6273(03)00597-x. View

14.

Gabbott P, Warner T, Jays P, Salway P, Busby S . Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol. 2005; 492(2):145-77. DOI: 10.1002/cne.20738. View

15.

Otis J, Namboodiri V, Matan A, Voets E, Mohorn E, Kosyk O . Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature. 2017; 543(7643):103-107. PMC: 5772935. DOI: 10.1038/nature21376. View

16.

Kim C, Ye L, Jennings J, Pichamoorthy N, Tang D, Yoo A . Molecular and Circuit-Dynamical Identification of Top-Down Neural Mechanisms for Restraint of Reward Seeking. Cell. 2017; 170(5):1013-1027.e14. PMC: 5729206. DOI: 10.1016/j.cell.2017.07.020. View

17.

Narayanan N, Laubach M . Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex. Neuron. 2006; 52(5):921-31. PMC: 3995137. DOI: 10.1016/j.neuron.2006.10.021. View

18.

Franklin T, Silva B, Perova Z, Marrone L, Masferrer M, Zhan Y . Prefrontal cortical control of a brainstem social behavior circuit. Nat Neurosci. 2017; 20(2):260-270. PMC: 5580810. DOI: 10.1038/nn.4470. View

19.

Hultman R, Ulrich K, Sachs B, Blount C, Carlson D, Ndubuizu N . Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. Cell. 2018; 173(1):166-180.e14. PMC: 6005365. DOI: 10.1016/j.cell.2018.02.012. View

20.

Spellman T, Rigotti M, Ahmari S, Fusi S, Gogos J, Gordon J . Hippocampal-prefrontal input supports spatial encoding in working memory. Nature. 2015; 522(7556):309-14. PMC: 4505751. DOI: 10.1038/nature14445. View