2019年10月13日(日) 14:50 〜 16:30 第17会場 (末広)

Organizer / Chair: Makoto TANIGUCHI (Department of Neuroscience, Medical University of South Carolina, USA), Co-chair: Kazuya IWAMOTO (Department of Molecular Brain Science, Kumamoto University, Japan), Discussants: ‌Naoko KUZUMAKI (Department of Pharmacology, Hoshi University, Japan), Akiyoshi SAITOH (Laboratory of Pharmacology, Faculty of Pharmaceutical Science, Tokyo University of Science, Japan)

Psychiatric disorders cause the significant burden to the individual and worldwide, and have been increasing on current human society. Psychiatric disorders such as drug addiction and stress-related illnesses including major depressive disorder, post-traumatic stress disorder, and anxiety disorder are complex multifactorial illnesses involving chronic alternations in the neuronal circuit that contribute to their pathophysiology. The diverse array of behavioral symptoms in the individuals make it difficult to decrease morbidity with efficacy therapies and identify any specific genes linking to the underlying causal of these diseases. While genetic factors play crucial roles in the etiology of mental illnesses, identical twin studies demonstrated the relatively high rates of discordance indicate the importance of additional mechanisms. Environmental factors such as stress or abuse of drugs are known to play significant roles in the development of psychiatric disorders. Repeated exposure with stressors or drugs extended beyond the significant period of times and traumatic event induce persistent changes in gene expression and neuronal circuit function that lead to long-lasting maladaptive behaviors. Increasing evidence indicates that dysregulation of epigenetic mechanisms and its crucial contribution in the pathophysiology in the psychiatric disorders. In this symposium, we will discuss the epigenetic mechanisms underlying the development of psychiatric disorders.
Epigenetic mechanisms control gene transcription without alternations of the DNA sequence itself, rather change the chromatin state. In the nucleus, DNA is packed into chromatin which is comprised of DNA and histones. The N-terminal histone tails can undergo many types of post-translational modifications including acetylation which often observed in the genomic region of the active state for transcription. The acetylation is controlled by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs transfer an acetyl group to a histone lysine residue, whereas HDACs remove. Acetylation of histone tail relaxes chromatin structure and produces space for the transcriptional machinery resulting in transcriptional active states. HDACs are classified into subgroups: Class I HDAC (HDAC1, 2, 3, and 8) consists of a central deacetylase domain and are mostly localized within the cell nucleus. They have well-described histone deacetylase enzymatic activity and are found in large gene repressor complexes. Class IIa HDACs (HDAC4, 5, 7, and 9) can be shuttled between cytoplasm and the nucleus. Although their enzymatic activity is unclear, the neuronal activity-dependent subcellular redistribution of class IIa HDACs regulates their interaction with transcription factors and recruits repressor complexes. The crucial roles of epigenetics have been suggested from clinical genetic and postmortem brain studies and preclinical pharmacological studies, further understanding of epigenetics is important to improve the efficacy of therapy and to decrease mortality of psychiatric disorders.
In this symposium, Dr. Taniguchi will discuss the regulatory mechanisms of class IIa HDACs in response to exposure to drugs, cocaine and heroin, and its function in the drug addiction-related behaviors. Dr. Uchida will discuss the epigenetic mechanisms of class I HDACs underlying vulnerability to stress-related psychiatric disorders. Dr. Maddox will discuss the role of class IIa HDACs, HDAC4, in the contribution of development of PTSD in women.