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.

Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia

“…With regard to cognition, iclepertin reversed MK-801-induced deficits in working memory in the spontaneous alternation task in mice and led to significant improvement of episodic memory function in social recognition in rats using a 24-hour forgetting paradigm (time interval between T1 and T2). Thus, this study demonstrates the ability of iclepertin to reverse deficits in clinically relevant EEG biomarkers and working memory in a rodent model of NMDA receptor hypofunction related to schizophrenia (Deserno et al, 2012;Gao et al, 2022). Iclepertin also improved recognition/episodic memory in naïve rats, a memory domain that is also impaired in patients with schizophrenia (Bonner-Jackson et al, 2005;Guo et al, 2019).…”

Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders

“…Alterations to this calcium channel are associated with depressive-like symptoms in the prefrontal cortex 86 , with the risk-associated SNP (rs1006737) correlated with increased cortical function during executive cognition and higher cortical CACNA1C mRNA levels during brain development 87 . GRIN2A was recently reported to be highly associated with schizophrenia in the largest exome-sequencing study to date 46 , and NMDA receptor hypofunction and the resultant glutamate dysregulation are among the most highly implicated and replicated finding in postmortem brain studies examining the schizophrenia cortex, thought to be intrinsically linked to dopamine neurotransmission and its dysfunction 88,89 . The NMDA receptor is composed of multiple subunits, with the composition of this receptor switching from containing the NR2B subunit to the NR2A ( GRIN2A ) subunit over development.…”

“…The NMDA receptor is composed of multiple subunits, with the composition of this receptor switching from containing the NR2B subunit to the NR2A ( GRIN2A ) subunit over development. Alterations in this subunit switch may alter the maturation of cortical circuits and lead to NMDA receptor hypofunction 88 . Further analysis of the core gene set could lead to new insights into schizophrenia and underpin the finding of a common basis in psychiatric disorders.…”

Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

“…Proton magnetic resonance spectroscopy (MRS) studies have revealed increased glutamine levels in the medial prefrontal cortex, anterior cingulate cortex, and thalamus in drug-naïve patients with firstepisode psychosis (36,37), suggesting dysregulation of glutamate neurotransmission (38). Moreover, reduced activation of the prefrontal cortices (i.e., hypofrontality) has been considered to underlie negative symptoms and cognitive deficits in schizophrenia (39)(40)(41). Notably, it has been proposed that antipsychotic medications may reduce NMDARs activity and produce dysfunctions in the corticolimbothalamic circuit and hypofrontality in patients with schizophrenia (42).…”