M4-mediated cholinergic transmission is reduced in parkinsonian mice and its restoration alleviates motor deficits and levodopa-induced dyskinesia

Abstract

The dynamic equilibrium between dopamine (DA) and acetylcholine (ACh) in the dorsal striatum is thought to be essential for motor function, as imbalances in their levels are associated with Parkinsons disease (PD) and levodopa-induced dyskinesia (LID). While loss of DA leads to enhanced striatal ACh, whether this translates to specific alterations in transmission remains unclear. To address this, we examined how the strength of ACh release and signaling onto direct-pathway medium spiny neurons is altered in parkinsonian mice. Rather than the predicted cholinergic enhancement, we found that the strength of muscarinic M4-receptor mediated transmission was reduced following DA loss, resulting from downregulated receptors and downstream signaling. Despite M4-receptors being thought to mediate anti-kinetic effects, restoring M4-receptor function partially rescued parkinsonian balance and coordination deficits and limited the development of levodopa-induced dyskinetic behaviors, indicating that decreased M4-function contributed to circuit and motor dysfunctions in response to DA loss.