title: D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons.
abstract: Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D2 dopamine receptor modulation of Na+ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D2 receptor activation led to a reduction in Na+ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na+ channels into the slow-inactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.
authors.affiliation: Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Maurice
authors.forename: Jeff
authors.initials: J
authors.lastname: Mercer
authors.forename: C Savio
authors.initials: CS
authors.lastname: Chan
authors.forename: Salvador
authors.initials: S
authors.lastname: Hernandez-Lopez
authors.forename: Joshua
authors.initials: J
authors.lastname: Held
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tkatch
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D065127:Dopamine D2 Receptor Antagonists; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D015640:Ion Channel Gating; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D021122:Protein Subunits; D017448:Receptors, Dopamine D2; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D000109:Acetylcholine