title: Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.
abstract: Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins including α-tubulin, Hsp90, and cortactin. Since robust expression of Hdac6 is observed in brain, it would be expected that Hdac6-mediated reversible acetylation plays essential roles in CNS. Here we demonstrate the crucial roles of Hdac6 deacetylase activity in the expression of emotional behavior in mice. We found that Hdac6-deficient mice exhibit hyperactivity, less anxiety, and antidepressant-like behavior in behavioral tests. Moreover, administration of Hdac6-specific inhibitor replicated antidepressant-like behavior in mice. In good agreement with behavioral phenotypes of Hdac6-deficient mice, Hdac6 dominantly localizes to the dorsal and median raphe nuclei, which are involved in emotional behaviors. These findings suggest that HDAC6-mediated reversible acetylation might contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression.
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.forename: Atsuko
authors.initials: A
authors.lastname: Hanai
authors.forename: Atsuo
authors.initials: A
authors.lastname: Nakayama
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
mesh_terms: D000107:Acetylation; D000818:Animals; D051356:Cortactin / Q000235:genetics / Q000378:metabolism; D004644:Emotions / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011903:Raphe Nuclei / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D051356:Cortactin; D018841:HSP90 Heat-Shock Proteins; D014404:Tubulin; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases