title: Modulation of direct pathway striatal projection neurons by muscarinic M₄-type receptors.
abstract: 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 D(1 or 2)-eGFP transgenic mice to show that activation of M4-type receptors with bath applied muscarine enhances Ca(2+)-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 Ca(2+)-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.
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Hernández-Flores
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Omar
authors.initials: O
authors.lastname: Hernández-González
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: María B
authors.initials: MB
authors.lastname: Pérez-Ramírez
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Esther
authors.initials: E
authors.lastname: Lara-González
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Arias-García
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Mariana
authors.initials: M
authors.lastname: Duhne
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Azucena
authors.initials: A
authors.lastname: Pérez-Burgos
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: G Aleph
authors.initials: GA
authors.lastname: Prieto
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Figueroa
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico.
authors.forename: Elvira
authors.initials: E
authors.lastname: Galarraga
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, PO Box 70-253, México City, DF 04510, Mexico. Electronic address: jbargas@ifc.unam.mx.
authors.forename: José
authors.initials: J
authors.lastname: Bargas
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology*; D004298:Dopamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009529:Nicardipine / Q000494:pharmacology; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D043588:Receptor, Muscarinic M4; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D009529:Nicardipine; D000109:Acetylcholine; D004298:Dopamine
keywords: Acetylcholine; Ca(V)1 Ca(2+)-channels; Excitability; Striatal projection neurons; Striatum