title: Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release.
abstract: 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 learning/control. The possible involvement of the CAPS2 gene in the cerebellar deficits of autistic patients is discussed.
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sadakata
authors.forename: Wataru
authors.initials: W
authors.lastname: Kakegawa
authors.forename: Akira
authors.initials: A
authors.lastname: Mizoguchi
authors.forename: Miwa
authors.initials: M
authors.lastname: Washida
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Katoh-Semba
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Shutoh
authors.forename: Takehito
authors.initials: T
authors.lastname: Okamoto
authors.forename: Hisako
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kazushi
authors.initials: K
authors.lastname: Kimura
authors.forename: Mika
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekine
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.forename: Soichi
authors.initials: S
authors.lastname: Nagao
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009411:Nerve Endings; D009412:Nerve Fibers; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons; D011689:Purkinje Cells; D020813:Receptor, trkB / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses
chemical_list: C480975:CAPS2 protein, mouse; C510820:Cadps protein, mouse; D002135:Calcium-Binding Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D020813:Receptor, trkB; D020812:Receptor, trkC