Metabotropic Glutamate Receptor–Dependent Synaptic Plasticity in Age-Related Neurodegenerative Disorders

Synaptic plasticity is a fundamental property of the nervous system that underpins learning, memory, and adaptive behavior across the lifespan. Disruption of plasticity mechanisms is increasingly recognized as a unifying feature of age-related neurodegenerative and neuropsychiatric disorders. While classical models of long-term potentiation (LTP) and long-term depression (LTD) have primarily emphasized ionotropic glutamate receptors (iGluRs), emerging evidence identifies metabotropic glutamate receptors (mGluRs) as central regulators of synaptic stability, metaplasticity, and activity-dependent translational control. This review synthesizes molecular, synaptic, circuit-level, and translational evidence to position mGluR–dependent plasticity as a context-sensitive signaling framework that governs excitatory–inhibitory balance across cortical and subcortical networks. This review examines subtype-specific contributions of Groups I, II, and III mGluRs to LTP and LTD, highlighting their roles in intracellular calcium dynamics, protein synthesis–dependent plasticity, and neuron–glia interactions. Particular emphasis is placed on receptor localization, intracellular signaling pathways, and region-specific cortical plasticity, which collectively determine how mGluR signaling shapes functional outcomes across distributed brain circuits. This review further discusses how dysregulation of mGluR–mediated plasticity contributes to synaptic and circuit dysfunction in Alzheimer’s disease (AD), Parkinson’s disease (PD), schizophrenia, autism spectrum disorder (ASD), Fragile X syndrome (FXS), and epilepsy, with attention to disease stage–specific and context-dependent alterations revealed by electrophysiological, molecular, and receptor imaging studies. Finally, emerging translational strategies, including subtype-selective biomarkers, allosteric and pathway-biased modulation, and circuit-targeted interventions, are evaluated for their potential to restore adaptive plasticity while limiting maladaptive network remodeling. Collectively, this review reframes mGluR–dependent synaptic plasticity as a dynamic and integrative regulator of neuronal circuit function in aging and disease, providing a conceptual and mechanistic foundation for the development of precision neuroplasticity-based therapeutics.