Targeting M4 muscarinic receptors for the treatment of L-Dopa-induced dyskinesia

The central aim of the proposed project is test the hypothesis that systemic administration of an M4R PAM will prevent abnormal potentiation of dSPN glutamatergic synapses and alleviate dyskinetic behavior in a mouse model of LID. Specifically, we hypothesize that: 1) M4Rs promote the induction of long-term depression (LTD) and depotentiation of dSPN glutamatergic synapses through both RGS4 (regulator of G protein signaling 4) dependent and independent mechanisms; and 2) M4R PAMs blunt aberrant, L-DOPA-evoked synaptic plasticity and reduce abnormal involuntary movements (AIM) following L-DOPA treatment in dyskinetic mice. The proposed studies rigorously pursue the role of dSPN M4Rs in health and PD using cuttingedge approaches that overcome previous experimental obstacles. These studies should provide a solid foundation for further translational studies aimed at developing adjunct therapies that alleviate LID.