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The Journal of Neuroscience, March 7, 2007, 27(10):2472-2482; doi:10.1523/JNEUROSCI.2279-06.2007

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Development/Plasticity/Repair
Impaired Cerebellar Development and Function in Mice Lacking CAPS2, a Protein Involved in Neurotrophin Release

Tetsushi Sadakata,¹ Wataru Kakegawa,⁵ Akira Mizoguchi,⁶ Miwa Washida,¹ Ritsuko Katoh-Semba,⁷ Fumihiro Shutoh,² Takehito Okamoto,² Hisako Nakashima,⁶ Kazushi Kimura,⁶ Mika Tanaka,³ Yukiko Sekine,¹ Shigeyoshi Itohara,⁴ Michisuke Yuzaki,⁵ Soichi Nagao,² and Teiichi Furuichi¹

¹Laboratory for Molecular Neurogenesis, ²Laboratory for Motor Learning Control, ³Research Resource Center, and ⁴Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, ⁵Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan, ⁶Department of Anatomy, School of Medicine, Mie University, Tsu, Mie 514-8507, Japan, and ⁷Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan

Correspondence should be addressed to Teiichi Furuichi, Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: tfuruichi{at}brain.riken.go.jp

Ca²⁺-dependent activator protein for secretion 2 (CAPS2/CADPS2) is a secretory granule-associated protein that is abundant at the parallel fiber terminals of granule cells in the mouse cerebellum and is involved in the release of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), both of which are required for cerebellar development. The human homolog gene on chromosome 7 is located within susceptibility locus 1 of autism, a disease characterized by several cerebellar morphological abnormalities. Here we report that CAPS2 knock-out mice are deficient in the release of NT-3 and BDNF, and they consequently exhibit suppressed phosphorylation of Trk receptors in the cerebellum; these mice exhibit pronounced impairments in cerebellar development and functions, including neuronal survival, differentiation and migration of postmitotic granule cells, dendritogenesis of Purkinje cells, lobulation between lobules VI and VII, structure and vesicular distribution of parallel fiber–Purkinje cell synapses, paired-pulse facilitation at parallel fiber–Purkinje cell synapses, rotarod motor coordination, and eye movement plasticity in optokinetic training. Increased granule cell death of the external granular layer was noted in lobules VI–VII and IX, in which high BDNF and NT-3 levels are specifically localized during cerebellar development. Therefore, the deficiency of CAPS2 indicates that CAPS2-mediated neurotrophin release is indispensable for normal cerebellar development and functions, including neuronal differentiation and survival, morphogenesis, synaptic function, and motor leaning/control. The possible involvement of the CAPS2 gene in the cerebellar deficits of autistic patients is discussed.

Key words: CAPS2/CADPS2; CAPS1/CADPS1; neurotrophin; BDNF; NT-3; cerebellum

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Received May 30, 2006; revised Jan. 23, 2007; accepted Jan. 27, 2007.

Correspondence should be addressed to Teiichi Furuichi, Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: tfuruichi{at}brain.riken.go.jp

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