Glutamate receptors as regulators of synaptic plasticity in neuropsychiatric disorders: pathological insight and...

Glutamate receptors (GluRs) are central regulators of synaptic plasticity, a fundamental physiological process underlying learning, memory, and adaptive behaviour. Synaptic plasticity is a dynamic process in which synapses undergo activity-dependent changes between the communicating neurons, forming the cellular basis of cognition. Dysfunctional synaptic plasticity can exacerbate neurological symptoms, thus underlying a broad spectrum of neuropsychiatric disorders (NPDs), including schizophrenia, major depressive disorder and bipolar disorder. Advancements in the field have highlighted that functional impairment in the GluR have heightened excitatory neurotransmission, thus disrupting synaptic transmission, leading to excitotoxicity and neuronal cell defects. These dysfunctions constitute the mechanistic basis of NPDs has prompted researchers to target various GluR families, namely ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The iGluRs are further subclassified into N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), kainate receptor (KAR), and delta glutamate receptor (GluD). Therapeutic modulation of these GluR is aimed at restoring the homeostatic balance between glutamatergic signalling and synaptic functions. This review provides a comprehensive overview of how dysregulation of these GluRs results in maladaptive synaptic plasticity, thus contributing to neuropsychiatric conditions as studied in in vitro, human, and animal models. Additionally, the review features the current therapeutic strategies targeting GluRs modulators in the amelioration of disease phenotype. By integrating the molecular and clinical insights, we advocate that GluRs represents a promising therapeutic target for the modulation of aberrant neural plasticity in NPDs.