In the last few years, our understanding of the signaling mechanism controlling synaptic plasticity in the corticostriatal circuits by ACh has expanded significantly. The muscarinic receptor signaling cascades outlined here are summarized in Figure 3. Several lines of evidence converge to suggest that muscarinic M1-like receptor signaling enhances dendritic excitability and spiking of striatal MSNs, whereas M2-like receptor exerts the opposite effect in shaping excitability. In line with this principle, recently, a class of mutated muscarinic receptors that can be activated non-invasively by synthetic ligands have been engineered [54]. Among these, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) [55] are modified muscarinic receptors that can no longer be activated by acetylcholine and can be activated instead by clozapine-N-oxide (CNO). The hM3Dq, modified M3 receptor is Gq coupled and is excitatory [56], whereas the modified M4, hM4D, is Gi coupled and inhibits firing [55,57].
