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

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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Fig. 1: Plot of PFC organization highlighting the functional mapping of some long-range and local circuits of PFC.
Fig. 2: Plot of PFC regulation illustrating some neurochemical influences on glutamatergic (Glu) excitation and GABAergic (GABA) inhibition in PFC neurons.
Fig. 3: Schematic diagram illustrating a potential mechanism underlying the social deficits in Shank3 autism models.
Fig. 4: Schematic diagram illustrating the synaptic changes in PFC of schizophrenia (SZ) and major depressive disorder (MDD).
Fig. 5: Schematic diagram illustrating the potential epigenetic mechanisms underlying gene dysregulation and synaptic deficits in PFC of AD.

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Acknowledgements

We are grateful to former and current members of Dr. Yan’s laboratory for their contributions to the original findings and NIH grants (MH108842, MH112237, DA037618, AG056060, AG064656 to ZY) for their support of some of the work reviewed here.

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Yan, Z., Rein, B. Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01092-3

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