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Aberrant maturation and connectivity of prefrontal cortex in schizophrenia—contribution of NMDA receptor development and hypofunction

Abstract

The neurobiology of schizophrenia involves multiple facets of pathophysiology, ranging from its genetic basis over changes in neurochemistry and neurophysiology, to the systemic level of neural circuits. Although the precise mechanisms associated with the neuropathophysiology remain elusive, one essential aspect is the aberrant maturation and connectivity of the prefrontal cortex that leads to complex symptoms in various stages of the disease. Here, we focus on how early developmental dysfunction, especially N-methyl-D-aspartate receptor (NMDAR) development and hypofunction, may lead to the dysfunction of both local circuitry within the prefrontal cortex and its long-range connectivity. More specifically, we will focus on an “all roads lead to Rome” hypothesis, i.e., how NMDAR hypofunction during development acts as a convergence point and leads to local gamma-aminobutyric acid (GABA) deficits and input-output dysconnectivity in the prefrontal cortex, which eventually induce cognitive and social deficits. Many outstanding questions and hypothetical mechanisms are listed for future investigations of this intriguing hypothesis that may lead to a better understanding of the aberrant maturation and connectivity associated with the prefrontal cortex.

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Fig. 1: Illustration showing the simplified local prefrontal circuitry and long-range input/output connectivity.
Fig. 2: Prefrontal local circuit.
Fig. 3: Schematic model showing the development of NMDAR subunits in different types of PFC neurons.
Fig. 4: Developmental trajectory of cortical GABAergic interneurons and maturation of MD and PFC.
Fig. 5: A summary illustration of the perspective mechanisms associated with dysconnectivity and behavioral deficits—from abnormal synaptic function and plasticity to failures of self-monitoring.

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Acknowledgements

This study was supported by NIH R21MH110678, the NIH R01MH085666, NARSAD Independent Award 2015, and Pennsylvania Commonwealth 4100072545 (CURE 2016) to WJG.

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WJG, SSY, NRM, and LAC wrote and edited the manuscript.

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Correspondence to Wen-Jun Gao.

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Gao, WJ., Yang, SS., Mack, N.R. et al. Aberrant maturation and connectivity of prefrontal cortex in schizophrenia—contribution of NMDA receptor development and hypofunction. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01196-w

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