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

• Published in: Molecular psychiatry Vol. 27; no. 1; pp. 731 - 743
• Main Authors: Gao, Wen-Jun, Yang, Sha-Sha, Mack, Nancy R., Chamberlin, Linda A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2022; Nature Publishing Group
• Subjects: 59/36; 631/378; 64/60; 692/699/476/1799; 9/30; 9/74; Behavioral Sciences; Biological Psychology; Cognitive ability; Connectivity; Expert Review; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Humans; Hypotheses; Maturation; Medicine; Medicine & Public Health; Mental disorders; N-Methyl-D-aspartic acid receptors; Nervous system; Neural networks; Neurosciences; Pharmacotherapy; Prefrontal cortex; Prefrontal Cortex - metabolism; Psychiatry; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia; Schizophrenia - genetics; Signal Transduction; γ-Aminobutyric acid
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01196-w

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.