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

In Parkinson’s disease (PD), imbalances in dorsal striatum (DSt) output pathways leading to motor dysfunction are thought to be driven by the loss of dopamine (DA) itself and the disruption of its coordinated modulation with acetylcholine (ACh). While the gradual decline of DA across striatal regions over time is a defining characteristic of PD, less is known about the adaptive and/or pathological alterations in cholinergic signaling that develop throughout disease progression in response to DA loss. 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, in order to model early and advanced stages of PD. We found a reduction in muscarinic M4 receptor signaling that began in the dorsolateral striatum (DLS) following a partial loss of DA, yet was not evident in the dorsomedial region (DMS) until the dopaminergic lesion was nearly complete. Combining electrophysiological, pharmacological and 2-photon imaging approaches, we determined that this decrease was the result of reduced postsynaptic M4 receptor function, and was not accounted for by changes in ACh release or clearance. Replacing the partial loss of endogenous DA with levodopa could not rescue the dysfunctional M4 receptors. Together, these findings reveal how changes in cholinergic modulation closely follow the temporal and regional pattern of dopaminergic degeneration, which is critical for understanding their shared role in PD progression, and for developing alternative therapeutic interventions.