Activator of KAT3 histone acetyltransferase family ameliorates a neurodevelopmental disorder phenotype in the syntaxin 1A ablated mouse model
Takahiro Nakayama,
Akash K. Singh,
Toshiyuki Fukutomi,
Noriyuki Uchida,
Yasuo Terao,
Hiroki Hamada,
Takahiro Muraoka,
Eswaramoorthy Muthusamy,
Tapas K. Kundu,
Kimio Akagawa
Affiliations
Takahiro Nakayama
Department of Medical Physiology, Kyorin University School of Medicine, Tokyo 181-8611, Japan; Corresponding author
Akash K. Singh
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India; Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India
Toshiyuki Fukutomi
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-8611, Japan
Noriyuki Uchida
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan
Yasuo Terao
Department of Medical Physiology, Kyorin University School of Medicine, Tokyo 181-8611, Japan
Hiroki Hamada
Department of Life Science, Okayama University of Science, Okayama 700-0005, Japan
Takahiro Muraoka
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan
Eswaramoorthy Muthusamy
Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India
Tapas K. Kundu
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India; Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India
Kimio Akagawa
Department of Medical Physiology, Kyorin University School of Medicine, Tokyo 181-8611, Japan
Summary: Syntaxin-1A (stx1a) repression causes a neurodevelopmental disorder phenotype, low latent inhibition (LI) behavior, by disrupting 5-hydroxytryptaminergic (5-HTergic) systems. Herein, we discovered that lysine acetyltransferase (KAT) 3B increases stx1a neuronal transcription and TTK21, a KAT3 activator, induces stx1a transcription and 5-HT release in vitro. Furthermore, glucose-derived CSP-TTK21 could restore decreased stx1a expression, 5-HTergic systems in the brain, and low LI in stx1a (+/−) mice by crossing the blood-brain barrier, whereas the KAT3 inhibitor suppresses stx1a expression, 5-HTergic systems, and LI behaviors in wild-type mice. Finally, in wild-type and stx1a (−/−) mice treated with IKK inhibitors and CSP-TTK21, respectively, we show that KAT3 activator-induced LI improvement is a direct consequence of KAT3B-stx1a pathway, not a side effect. In conclusion, KAT3B can positively regulate stx1a transcription in neurons, and increasing neuronal stx1a expression and 5-HTergic systems by a KAT3 activator consequently improves the low LI behavior in the stx1a ablation mouse model.
