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

• Published in: Neuropharmacology 2015-02, Vol.89, p.232-244
• Main Authors: Hernández-Flores, Teresa, Hernández-González, Omar, Pérez-Ramírez, María B., Lara-González, Esther, Arias-García, Mario A., Duhne, Mariana, Pérez-Burgos, Azucena, Prieto, G. Aleph, Figueroa, Alejandra, Galarraga, Elvira, Bargas, José
• Format: Article
• Language: English
• Subjects: Acetylcholine; Acetylcholine - pharmacology; Animals; Calcium Channel Blockers - pharmacology; CaV1 Ca2+-channels; Cells, Cultured; Corpus Striatum - cytology; Dopamine - pharmacology; Excitability; In Vitro Techniques; Male; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Transgenic; Neural Pathways - drug effects; Neural Pathways - physiology; Neurons - drug effects; Neurons - physiology; Nicardipine - pharmacology; Receptor, Muscarinic M4 - metabolism; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D2 - genetics; Sodium Channel Blockers - pharmacology; Striatal projection neurons; Striatum; Tetrodotoxin - pharmacology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.09.028

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 D1-type DA, M1-and M4-type ACh receptors, while iSPNs express D2-type DA and M1-type ACh receptors. Actions of M1-, D1-, and D2-receptors have been extensively reported, but we still ignore most actions of muscarinic M4-type receptors. Here, we used whole-cell recordings in acutely dissociated neurons, pharmacological tools such as mamba-toxins, and BAC D1or2-eGFP transgenic mice to show that activation of M4-type receptors with bath applied muscarine enhances Ca2+-currents through CaV1-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 M4-type receptors. M4-receptor activation also increased network activity of dSPNs but not of iSPNs as seen with calcium-imaging techniques. Moreover, actions of D1-type and M4-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. •Activation of M4-type receptors enhances Ca2+-current in striatal neurons.•Enhanced Ca2+-current is carried by CaV1 channels.•Enhanced Ca2+-current increased evoked discharge after current injection or synaptic stimulation.•M4-receptor actions interact with D1-receptor actions.•These actions only occur in direct pathway striatal neurons.