NMDA Receptor Dysfunction and Cognitive Impairment in Schizophrenia: Mechanisms, Evidence and Therapeutic Potential

Wanqing Xu

doi:10.62051/8ya7t590

Authors

Wanqing Xu

DOI:

https://doi.org/10.62051/8ya7t590

Keywords:

Schizophrenia, cognitive impairment, therapeutic potential, NMDA receptor.

Abstract

Cognitive impairment is a defining and functionally disabling symptom of schizophrenia, consisting of deficits in executive function, working memory, and social cognition. These deficits are pervasive throughout stages of illness and are poorly remediated by current pharmacological treatments. Accumulating evidence implicates N-methyl-D-aspartate (NMDA) receptor hypofunction as a critical mechanism in these cognitive symptoms. This article synthesizes findings from behavioral, neuroimaging, genetic, pharmacological and animal model studies to explore how NMDA receptor dysfunction destabilizes prefrontal and hippocampal circuits, disrupts synaptic plasticity, and impairs cortical synchrony underlying cognitive processes. It also addresses the therapeutic potential of NMDA-targeted treatments such as co-agonist supplementation and glycine transporter inhibition, while highlighting inconsistencies in clinical efficacy and the contribution of individual variability—including genetic polymorphisms and neurochemical profiles—to treatment response. The review also addresses translational limitations of current animal models and the need for more human-relevant studies. Based on these findings, the paper argues for larger-scale, biomarker-driven clinical trials, genetically informed stratification strategies, and cross-disciplinary collaboration towards the development of precision interventions against the cognitive core of schizophrenia.

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