title: Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia.
abstract: Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos+D2 MSNs and decreased c-Fos+non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD.
authors.affiliation: Center for Health Sciences, Bioscience Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Tanuja
authors.initials: T
authors.lastname: Bordia
authors.affiliation: Center for Health Sciences, Bioscience Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Danhui
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Center for Health Sciences, Bioscience Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Xiomara A
authors.initials: XA
authors.lastname: Perez
authors.affiliation: Center for Health Sciences, Bioscience Division, SRI International, Menlo Park, CA 94025, USA. Electronic address: maryka.quik@sri.com.
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D000075402:Channelrhodopsins; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000633:toxicity; D008297:Male; D008409:Mastication / Q000187:drug effects; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009538:Nicotine / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000627:therapeutic use; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D000071057:Tardive Dyskinesia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*
chemical_list: D014150:Antipsychotic Agents; D000075402:Channelrhodopsins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D017448:Receptors, Dopamine D2; D008464:Mecamylamine; D009538:Nicotine; D002795:Choline O-Acetyltransferase; D006220:Haloperidol
keywords: Cholinergic interneurons; D2 receptor-expressing neurons; GABAergic medium spiny neurons; Striatum; Tardive dyskinesia