AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication
Kunihiko Yamashiro,
Kei Hori,
Esther S.K. Lai,
Ryo Aoki,
Kazumi Shimaoka,
Nariko Arimura,
Saki F. Egusa,
Asami Sakamoto,
Manabu Abe,
Kenji Sakimura,
Takaki Watanabe,
Naofumi Uesaka,
Masanobu Kano,
Mikio Hoshino
Affiliations
Kunihiko Yamashiro
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan; Department of NCNP Brain Physiology and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Kei Hori
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan; Corresponding author
Esther S.K. Lai
Brain Mechanism for Behavior Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan; Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Ryo Aoki
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan; Department of NCNP Brain Physiology and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Kazumi Shimaoka
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan
Nariko Arimura
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan
Saki F. Egusa
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan
Asami Sakamoto
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan
Manabu Abe
Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Kenji Sakimura
Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Takaki Watanabe
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Naofumi Uesaka
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Cognitive Neurobiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Masanobu Kano
Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Mikio Hoshino
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan; Department of NCNP Brain Physiology and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Corresponding author
Summary: Autism susceptibility candidate 2 (AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development. Auts2 conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression of Cacna1a. Auts2 cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses and restriction of parallel fiber synapse numbers. Auts2 cKO mice exhibited behavioral impairments in motor learning and vocal communications. Because Cacna1a is known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.
