Molecular mechanisms of rapid antidepressant action induced by histone deacetylase inhibitor

Abstracts / Neuroscience Research 71S (2011) e108–e415

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P3-v13 Genetic association and postmortem studies of Dserine modulator PAPST1 in schizophrenia

P3-t03 Molecular mechanisms of rapid antidepressant action induced by histone deacetylase inhibitor

Akihito Uezato 1 , Dai Shimazu 1 , Naoki Yamamoto 1 , Robert E. McCullumsmith 2 , James H. Meador-Woodruff 2 , Toru Nishikawa 1

Teruyuki Hobara , Shusaku Uchida, Fumihiro Higuchi, Naoko Abe, Tomohiko Shibata, Koji Otsuki, Hirotaka Yamagata, Yoshifumi Watanabe

1

Sec. of Psych. and Bahav. Neurosci., Tokyo Med. and Dent. Univ., Tokyo, Japan Dept. of Psych and Behav. Neurobiol., University of Alabama at Birmingham, AL, USA 2

Div. of Neuropsy, Dept. Neurosci, Grad. Sch. of Med, Yamaguchi Univ., Ube, Japan

Hypofunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor-mediated neurotransmission has been hypothesized to underlie the pathophysiology of schizophrenia. NMDA receptor activity is modulated by D-serine in the presence of glutamate. In the present study, we examined the genetic association between PAPST1 (3 -Phsophoadenosine 5 Phosphosulfate Transporter 1), a D-serine modulator, and schizophrenia. In addition, we investigated the changes in mRNA expression of PAPST1 using the postmortem brain of patients with schizophrenia. In the case–control genetic association study comprising 233 control subjects and 237 patients with schizophrenia, the allele frequencies of the SNP rs9394996 were significantly different between the groups (p = 0.0452). In the postmortem brain study comprising 29 control subjects of 37 patients with schizophrenia, we found decreased mRNA expression of PAPST1 gene in the gray matter of the brains of female patients with schizophrenia. These results suggest that the genomic and/or transcriptional alteration of PAPST1 gene might be involved in the pathophysiology of schizophrenia. Research fund: Test.

Recent reports have suggested that epigenetic gene regulations, including histone modifications, are closely associated with the development of stress vulnerability, and also contribute to behavioral responses to chronic stress and antidepressants. There is evidence suggesting that histone deacetylase (HDAC) inhibitors have modest antidepressant-like effects in rodents. However, molecular mechanisms of antidepressant actions induced by HDAC inhibitors remain unclear. The purpose of this study is to clarify molecular mechanisms of antidepressant actions by HDAC inhibitors in vivo and in vitro. First, we confirmed the antidepressant efficacy of HDAC inhibitor SAHA using the mouse model of depression. We found that subchronic treatment with SAHA reversed the increased depression-like behaviors in mice subjected to chronic stress. In addition, subchronic treatment with SAHA enhanced the expression of calcium/calmodulin-dependent protein kinase (CaMK) II ␤ mRNA in the hippocampus of stressed mice. However, subchronic treatment with imipramine did not affect the expression of CaMKII ␤, as well as depression-like behaviors in stressed mice. These data suggest that SAHA has rapid antidepressant actions, and that the induction of CaMKII ␤ by SAHA may contribute to the antidepressant actions. We also found that subchronic treatment with SAHA enhanced adult neurogenesis in the dentate gyrus of the hippocampus. Furthermore, cell culture experiments showed the induction of CaMKII ␤ mRNA and the increased number of differentiated cells by HDAC inhibitors. Importantly, CaMKII ␤ knockdown inhibited the induction of cell differentiation by HDAC inhibitors. Thus our data suggest that the induction of CaMKII ␤ by HDAC inhibitors might be involved in structural plasticity and subsequent behavioral responses to chronic stress.

doi:10.1016/j.neures.2011.07.1311

P3-t02 Effects of chronic corticosterone administration in anxiety/depression-like behavior: A study using Ca2+ dependent activator protein for secretion 2 (Caps2) mutant mice Yuriko Mishima 1,2 , Tetsushi Sadakata 2,3 , Ritsuko Semba 1,2 , Chihiro Saruta 1 , Teiichi Furuichi 1,2,4

Katoh-

doi:10.1016/j.neures.2011.07.1313

1

Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Saitama, Japan 2 CREST, Saitama, Japan 3 Advanced Scientific Research Leaders Development Unit, Gunma University, Gunma, Japan 4 Faculty of Sciences and Technology, Tokyo University of Science, Chiba, Japan Depression and anxiety are the most common forms of mental illness. The symptoms are complex and the pathophysiologies are not fully understood. Several studies have shown that anxiety/depressive patients have prolonged activation of hypothalamic–pituitary–adrenal (HPA) axis, leading to increased level of stress hormone, cortisol. Although numerous animal models have been developed, analyses of anxiety/depression-related behaviors in these models gave mixed findings. Thus, neurobiology and genetic causes of the disorders are incompletely understood. Ca2+ -dependent activator protein for secretion 2 (CAPS2) is a member of the CAPS/CADPS protein family which regulates dense-core vesicle exocytosis, including BDNF. BDNF is implicated in anxiety/depression, since it is down- or upregulated by stress or antidepressant treatment, respectively. Additionally, Caps2 gene-deficient mice exhibit abnormal social behaviors. These results indicate that Caps2 mutant mice are useful animal models to study the neurobiological causes of mental disorders, such as anxiety/depression. In this study, corticosterone (CORT, cortisol in rodents) was administrated chronically via drinking water in both wild-type and Caps2 mutant mice. During the 7 week exposure of CORT, food, drinking consumption, and mouse body weight were monitored. Then, mice were subjected to anxiety/depression-related behavioral tests. After the behavioral tests, selected mouse brain regions were dissected to determine levels of BDNF and NT-3 proteins by the two-site enzymeimmunoassay systems. Preliminarily results from the behavioral tests and neurotrophin quantifications indicated that prolonged exposure to CORT tended to cause anxiety/depressive-like phenotype. On the other hand, rapid body weight gain was observed in the wild-type but not in the Caps2 mutant mice, which suggests differential response to CORT. Further experiments are currently in progress. Research fund: CREST. doi:10.1016/j.neures.2011.07.1312

P3-t04 Inhibition of deacetylase activity of Hdac6 causes antidepressant-like behavior in mice Masahide Fukada , Atsuko Hanai, Eiko Aoki, Kyoko Takeshima, Atsuo Nakayama, Yoshiharu Kawaguchi Div of Embryology, Inst for Dev Res, Aichi Human Service Center, Kasugai, Japan 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, biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of histone deacetylases (HDACs) family, is a unique deacetylase which localizes to cytoplasm, and functions in many cellular event by deacetylating non-histone proteins including ␣-tubulin, Hsp90, and cortactin. Since Hdac6 is expressed in brain exclusively, it would be expected that Hdac6-mediated 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 major sources of serotonin projections in brain. These findings provide an important prospect that HDAC6-mediated reversible acetylation in serotonergic neuron becomes as a new therapeutic target for the depression. Research fund: KAKENHI22700408. doi:10.1016/j.neures.2011.07.1314