Altered mGluR1/5-driven plasticity in the motor cortical surface as a biomarker for Parkinson’s disease

Abstract Parkinson’s disease (PD), a neurodegenerative disorder, is caused by dopaminergic lesions in the substantia nigra pars compacta that lead to motor deficits. Although metabotropic glutamate receptors (mGluRs) are key regulators of synaptic plasticity, their contribution to cortical surface long-term depression (LTD) in PD remains unknown. We used the 6-hydroxydopamine (6-OHDA) rat model of PD to examine synaptic plasticity in the primary motor cortex (M1) surface. Extracellular field recordings revealed that mGluR-dependent LTD induced by paired-pulse low-frequency stimulation (pp-LFS) was markedly reduced in PD rats, whereas N-methyl-D-aspartate receptor (NMDAR)-dependent LTD remained unchanged. Whole-cell patch-clamp recordings showed altered action potential (AP) kinetics, such as narrower spike half-widths and faster repolarization, in PD neurons on the M1 surface, suggesting that reduced LTD and sharper AP kinetics contribute to motor deficits. Combined with previous evidence of enhanced mGluR1/5-dependent long-term potentiation (LTP) in PD, these results indicate the involvement of a selective disruption of mGluR-mediated plasticity in maladaptive plasticity and motor dysfunction. Our study highlights group I mGluRs as both key modulators of sensorimotor homeostasis and potential therapeutic targets for restoring the synaptic balance following alteration by sensorimotor deficits.