Glutamatergic Dysregulation in Depression, Schizophrenia, and Addiction: Mechanisms and Therapeutic Strategies

Abstract

Glutamate, the principal excitatory neurotransmitter in the brain, plays a central role in neurotransmission, synaptic plasticity, and cognitive function. Dysregulation of glutamatergic signaling is implicated in depression, schizophrenia (SCZ), and addiction. N-methyl-Daspartate receptor/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (NMDAR/AMPAR) abnormalities and neuroinflammation disrupt synaptic plasticity in depression. NMDARs hypofunction and cortical excitation-inhibition imbalance are involved in SCZ. Therapeutic strategies targeting the glutamate system, including receptor modulation, glial function restoration, and inflammation control, offer promising avenues for treatment. However, their successful clinical application will require overcoming key obstacles such as disease heterogeneity, the lack of reliable biomarkers for these diseases, and stage-specific pathophysiological differences.