N‑methyl‑D‑aspartate receptor dysregulation as a neuromarker of schizophrenia: A narrative review

Schizophrenia is a severe neurodevelopmental disorder characterized by positive, negative, and cognitive symptoms. Emerging evidence implicates N‑methyl‑D‑aspartate receptor hypofunction in its pathophysiology, suggesting both mechanistic and biomarker potential. This comprehensive literature review was conducted using PubMed to identify clinical, neuroimaging, biochemical, genetic, and epigenetic studies examining N‑methyl‑D‑aspartate receptor dysregulation in schizophrenia. Articles spanning experimental models, patient cohorts, and postmortem analyses were screened and integrated. As a result, neuroimaging studies demonstrate that impaired prefrontal N‑methyl‑D‑aspartate receptor‑mediated control correlates with exaggerated striatal dopamine release. Peripheral assays consistently reveal reduced levels of key N‑methyl‑D‑aspartate receptor co‑agonists (d‑serine, glycine) and distinct metabolite correlation patterns in patients, offering minimally invasive biomarker candidates. Postmortem and neurovascular investigations extend receptor hypofunction beyond neurons, identifying deficient microglial quinolinic acid synthesis and endothelial N‑methyl‑D‑aspartate receptor deficits linked to cerebral hypoperfusion. Genetic and linkage analyses indicate polygenic contributions from N‑methyl‑D‑aspartate receptor subunit loci, whereas epigenetic silencing of N-methyl- D -aspartate receptor subunit 2B during development provides a mechanism for persistent receptor deficits. Convergent evidence establishes N‑methyl‑D‑aspartate receptor hypofunction as a robust marker of schizophrenia, with diagnostic, stratification, and therapeutic implications. Future research should prioritize validation of peripheral co‑agonist assays, in vivo functional imaging of N‑methyl‑D‑aspartate receptor activity, and clinical trials of receptor‑restorative agents to enable precision‑medicine approaches in schizophrenia.