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 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 the 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 on 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 treatment of human patients with these brain disorders.

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Microdeletion of the human 16p11.2 gene locus has been linked to autism spectrum disorder (ASD) and intellectual disability and confers risk for a number of other neurodevelopmental deficits. Transgenic mice carrying 16p11.2 deletion () display phenotypes reminiscent of those in human patients with 16p11.2 deletion syndrome, but the molecular mechanisms and treatment strategies for these phenotypes remain unknown. In this study, we have found that both male and female mice exhibit deficient NMDA receptor (NMDAR) function in the medial prefrontal cortex (mPFC), a brain region critical for high-level "executive" functions. Elevating the activity of mPFC pyramidal neurons with a CaMKII-driven Gq-DREADD (Gq-coupled designer receptors exclusively activated by designer drugs) led to the significant increase of NR2B subunit phosphorylation and the restoration of NMDAR function, as well as the amelioration of cognitive and social impairments in mice. These results suggest that NMDAR hypofunction in PFC may contribute to the pathophysiology of 16p11.2 deletion syndrome and that restoring PFC activity is sufficient to rescue the behavioral deficits. The 16p11.2 deletion syndrome is strongly associated with autism spectrum disorder and intellectual disability. Using a mouse model carrying the 16p11.2 deletion, , we identified NMDA receptor hypofunction in the prefrontal cortex (PFC). Elevating the activity of PFC pyramidal neurons with a chemogenetic tool, Gq-DREADD, led to the restoration of NMDA receptor function and the amelioration of cognitive and social impairments in mice. These results have revealed a novel route for potential therapeutic intervention of 16p11.2 deletion syndrome.

The human 16p11.2 gene locus is a hot-spot for copy number variations which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2 dp/+ ) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2 dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity or motor impairment. Electrophysiological recordings of 16p11.2 dp/+ mice found the deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2 dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2 dp/+ mice ameliorated the social and cognitive deficits and reversed the GABAergic synaptic impairment and neuronal hyper-excitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.