Postsynaptic adaptations in direct pathway muscarinic M4-receptor signaling follow the temporal and regional pattern of dopaminergic degeneration

Inn Parkinson’s disease (PD), imbalances in dorsal striatum pathways are thought to lead to motor dysfunction due to loss of dopamine (DA) and the disruption of coordinated modulation with acetylcholine (ACh). Here, we examined changes in cholinergic modulation of striatal direct pathway medium spiny neurons (dMSNs) in mice that were partially or completely depleted of DA, to model early and advanced stages of PD. We found a reduction in muscarinic M4 receptor signaling in the dorsolateral striatum (DLS) following partial DA loss of DA, which was not evident in the dorsomedial region (DMS) until DA loss was nearly complete. This decrease resulted from reduced postsynaptic M4 receptor function, as ACh release or clearance was unaffected, and could not be rescued by L-DOPA. These findings reveal how changes in cholinergic modulation follow the temporal and regional pattern of dopaminergic degeneration, which is critical for understanding their shared role in PD progression.