Cholinergic Transmission at Muscarinic Synapses in the Striatum Is Driven Equally by Cortical and Thalamic Inputs

The release of acetylcholine from cholinergic interneurons (Chls) directly modulates striatal output via muscarinic receptors on medium spiny neurons (MSNs). While thalamic inputs provide strong excitatory input to Chls, cortical inputs primarily regulate MSN firing. Here, we found that, while thalamic inputs do drive Chl firing, a subset of Chls responds robustly to stimulation of cortical inputs as well. To examine how input-evoked changes in Chl firing patterns drive acetylcholine release at cholinergic synapses onto MSNs, muscarinic M4-receptor-mediated synaptic events were measured in MSNs overexpressing G-protein gated potassium channels (GIRK2). Stimulation of both cortical and thalamic inputs was sufficient to equally drive muscarinic synaptic events in MSNs, resulting from the broad synaptic innervation of the stimulus-activated Chl population across many MSNs. Taken together, this indicates an underappreciated role for the extensive cholinergic network, in which small populations of Chls can drive substantial changes in post-synaptic receptor activity across the striatum.