title: Inhibition of histone deacetylases enhances the function of serotoninergic neurons in organotypic raphe slice cultures.
abstract: Inhibition of histone deacetylases (HDACs) is a promising approach for the treatment of mood disorders. However, the effects of HDAC inhibition on the serotonin (5-HT) system, a common target for psychiatric disorders, are poorly understood. Here, we show that a broad-spectrum HDAC inhibitor, trichostatin A (TSA), enhances the function of 5-HT neurons in organotypic raphe slice cultures. Sustained treatment with TSA (1μM) for 2 or 4 days significantly increased the 5-HT tissue content and tryptophan hydroxylase 2 (TPH2) expression, which were accompanied by hyper-acetylation of histone H3 in the promoter region of the TPH2 gene. TSA treatment for 4 days increased the extracellular 5-HT level, which was significantly suppressed in the presence of the selective AMPA receptor (AMPAR) antagonist NBQX. Moreover, the expression of both the AMPAR subunit GluA2 and Ca(2+)/calmodulin-dependent kinase II α (CaMKIIα) mRNAs were significantly increased by TSA treatment. Co-treatment with the CaMKII inhibitors KN-62 and KN-93 prevented the TSA-induced increase in 5-HT release, but had no effect on the increases in 5-HT tissue content. These results suggest that inhibition of HDACs increases 5-HT synthesis and release by epigenetic mechanisms, and that 5-HT release is mediated by the enhancement of AMPAR-mediated excitatory inputs and CaMKII signaling.
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Nozomi
authors: N
authors: Asaoka
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors: Kazuki
authors: K
authors: Nagayasu
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Naoya
authors: N
authors: Nishitani
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Mayumi
authors: M
authors: Yamashiro
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Hisashi
authors: H
authors: Shirakawa
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan. Electronic address: tknakaga@kuhp.kyoto-u.ac.jp.
authors: Takayuki
authors: T
authors: Nakagawa
authors: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors: Shuji
authors: S
authors: Kaneko
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017470:Receptors, Glutamate; D012701:Serotonin; C012589:trichostatin A; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: AMPA receptor; Ca(2+)/calmodulin-dependent kinase II; Histone deacetylase; Raphe slice cultures; Serotonin; Trichostatin A