title: Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.
abstract: Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
authors: Aryn H
authors: AH
authors: Gittis
authors: Daniel K
authors: DK
authors: Leventhal
authors: Benjamin A
authors: BA
authors: Fensterheim
authors: Jeffrey R
authors: JR
authors: Pettibone
authors: Joshua D
authors: JD
authors: Berke
authors: Anatol C
authors: AC
authors: Kreitzer
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D018680:Cholinergic Antagonists / Q000009:adverse effects; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020820:Dyskinesias / Q000209:etiology* / Q000473:pathology*; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007395:Interneurons / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D008297:Male; D008464:Mecamylamine / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D012601:Scopolamine / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018680:Cholinergic Antagonists; D018691:Excitatory Amino Acid Antagonists; C110702:IEM 1460; C498504:LHX6 protein, mouse; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D008464:Mecamylamine; D012601:Scopolamine; D000218:Adamantane