Targeting mGluR7 in Parkinson's disease: a novel approach to neuroprotection and synaptic therapies.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the substantia nigra pars compacta (SNPC) and complex motor and non-motor symptoms. Emerging evidence underscores excitotoxic glutamatergic overactivity as a key pathological driver of neurodegeneration, in addition to neuronal loss caused by dopamine depletion. Among the metabotropic glutamate receptors (mGluRs), mGluR7, a presynaptically located G protein-coupled receptor, has gained significant attention due to its unique low-affinity and high-threshold profile, which allows for selective modulation during synaptic hyperactivity while preserving physiological neurotransmission. mGluR7 is a glutamate sensor and inhibitor of glutamate release, modulating excitotoxicity, neuroinflammation, synaptic plasticity, and mitochondrial integrity, which are key features of PD neuropathology. It is highly expressed in basal ganglia loops and glial cells, providing dual-regulatory functionality in neuronal and immune microenvironments. Positive allosteric modulators of mGluR7 represent a potentially exciting group of compounds to increase receptor activity specifically during hyperglutamatergic conditions. In addition to monotherapy, mGluR7 modulators have significant value in the context of combined or stratified therapies, since they enhance dopaminergic therapy and restore synaptic dysfunction. Moreover, current developments in CRISPR-Cas9, RNAi, viral vectors, and nanomedicine offer new arenas to regulate mGluR7 expression and activity with precision. Translating preclinical success into clinical therapies is now feasible with advances in mGluR7-specific PET tracers, biomarkers, and patient profiling. Together, these findings position mGluR7 as a highly promising therapeutic target. This review critically explores the molecular structure, signaling mechanisms, and CNS distribution of mGluR7 by highlighting its role in modulating excitotoxicity, synaptic dysfunction, neuroinflammation, and mitochondrial stress in PD. It also examines the pharmacological development of mGluR7-targeted agents, their preclinical effects on motor and non-motor symptoms, and their potential in combination therapies. Emerging strategies such as CRISPR, RNAi, nanomedicine, and the development of mGluR7-specific biomarkers and imaging tools are also explored to support precision medicine in PD.