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.