title: Dopaminergic abnormalities in Hdac6-deficient mice.
abstract: Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular basis will lead to new insights into relations between protein acetylation events and psychiatric disorders. Here we report the dopaminergic abnormalities in Hdac6 KO mice. The dopamine transmission mediated by D1-like and D2-like G protein-coupled dopamine receptors is known to play roles in controlling movement, cognition, and motivational processes, and its dysfunction causes psychiatric disorders. We found that Hdac6 KO mice showed significantly increased locomotor response to novel, but not to habituated environment. In addition, Hdac6 KO mice showed a long-lasting sensitivity to psychostimulants, increased locomotor response to D2-like, but not D1 dopamine receptor agonists, and rapid locomotor response to apomorphine, a direct dopamine agonist, in dopamine-depleted condition. Hdac6 protein was expressed in dopaminergic neurons and their terminals in adult mice brain, and Hdac6-depletion augmented acetylation levels of dopamine-enriched synaptosomal proteins. In Hdac6 KO mice, the striatal content of dopamine and its metabolites was normal in basal condition, but mRNA level of D2 dopamine receptor in the striatum was decreased by 30%. Taken together, our results provide evidence that Hdac6 deficiency leads to aberrant dopamine-dependent behaviors by enhancing postsynaptic dopamine D2 receptor response. This study points out the possibility that Hdac6 and reversible-acetylation events play a regulatory role in D2 dopamine receptor signaling, and thus participate in the pathology of the dopamine-related psychiatric disorders such as schizophrenia.
authors.affiliation: Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukada
authors.affiliation: Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Aichi, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, North Carolina, USA.
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.affiliation: Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan. Electronic address: kawag001@inst-hsc.jp.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000073864:Histone Deacetylase 6 / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D012559:Schizophrenia
chemical_list: D000697:Central Nervous System Stimulants; C000600618:DRD2 protein, mouse; D015259:Dopamine Agents; C583261:Drd1 protein, mouse; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D008694:Methamphetamine; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D001058:Apomorphine; D004298:Dopamine
keywords: Dopamine; Dopamine receptors; Histone deacetylase 6; Protein acetylation; Schizophrenia