Astrocytes and metabotropic glutamate receptor 5 (mGluR5) have emerged as pivotal regulators of synaptic homeostasis and neural communication within the central nervous system (CNS). Although mGluR5 has long been considered neuron-specific, its functional expression in astrocytes is now recognized as essential for calcium (Ca2+) signaling, gliotransmission, and the modulation of synaptic plasticity. Dysregulation of astrocytic mGluR5 is increasingly implicated in the pathophysiology of neurodegenerative and psychiatric disorders including Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and schizophrenia (SCZ) by promoting neuroinflammation, excitotoxicity, and synaptic dysfunction. In this review, we explore the emerging role of astrocytic mGluR5 in mediating astrocyte-neuron communication and its maladaptive regulation in disease contexts. We also assess the therapeutic potential of targeting astrocytic mGluR5, highlighting advances in pharmacological modulators, gene therapy, and RNA-based strategies aimed at restoring homeostatic function. Despite recent progress, critical knowledge gaps remain, particularly regarding the regional specificity of astrocytic mGluR5 effects, its crosstalk with other signaling pathways, and its contribution to chronic neuroinflammation. Addressing these challenges may unlock innovative astrocyte-targeted therapies to restore synaptic integrity and protect against neurodegeneration in CNS disorders.
