Modulation of direct pathway striatal projection neurons by muscarinic M4-type receptors

Models of basal ganglia (BG) function posit a dynamic balance between two classes of striatal projection neurons (SPNs): direct pathway neurons (dSPNs) that facilitate movements, and indirect pathway neurons (iSPNs) that repress movement execution. Two main modulatory transmitters regulate the output of these neurons: dopamine (DA) and acetylcholine (ACh). dSPNs express D-1-type DA, M-1-and M-4-type ACh receptors, while iSPNs express D-2-type DA and M-1-type ACh receptors. Actions of M-1-, D-1-, and D-2-receptors have been extensively reported, but we still ignore most actions of muscarinic M-4-type receptors. Here, we used whole-cell recordings in acutely dissociated neurons, pharmacological tools such as mamba-toxins, and BAC D-1 or (2)-eGFP transgenic mice to show that activation of M-4-type receptors with bath applied muscarine enhances Ca2+-currents through Ca(v)1-channels in dSPNs and not in iSPNs. This action increases excitability of dSPNs after both direct current injection and synaptically driven stimulation. The increases in Ca2+-current and excitability were blocked specifically by mamba toxin-3, suggesting mediation via M-4-type receptors. M-4-receptor activation also increased network activity of dSPNs but not of iSPNs as seen with calcium-imaging techniques. Moreover, actions of D-1-type and M-4-type receptors may add to produce a larger enhancement of excitability of dSPNs or, paradoxically, oppose each other depending on the order of their activation. Possible implications of these findings are discussed. (C) 2014 Elsevier Ltd. All rights reserved.