title: Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.
abstract: In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, β2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation-reared mice.
authors.affiliation: Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: r-araki@pharm.setsunan.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Araki
authors.affiliation: Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hiraki
authors.affiliation: Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Nishida
authors.affiliation: Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kuramoto
authors.affiliation: Division of Medicinal Pharmacology Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Kinzo
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: yabe@pharm.setsunan.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yabe
mesh_terms: D000374:Aggression / Q000502:physiology; D000818:Animals; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D018682:GABA Agents / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics* / Q000378:metabolism*; D012934:Social Isolation / Q000523:psychology; D013550:Swimming / Q000523:psychology
chemical_list: D018682:GABA Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C453101:carboxyphenylglycine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D005998:Glycine
keywords: DNA methylation; Dorsal raphe nucleus; GABAB receptor; Histone acetylation; Isolation rearing; Social stimulation