title: Axonal localization of Ca2+-dependent activator protein for secretion 2 is critical for subcellular locality of brain-derived neurotrophic factor and neurotrophin-3 release affecting proper development of postnatal mouse cerebellum.
abstract: Ca2+-dependent activator protein for secretion 2 (CAPS2) is a protein that is essential for enhanced release of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. We previously identified dex3, a rare alternative splice variant of CAPS2, which is overrepresented in patients with autism and is missing an exon 3 critical for axonal localization. We recently reported that a mouse model CAPS2Δex3/Δex3 expressing dex3 showed autistic-like behavioral phenotypes including impaired social interaction and cognition and increased anxiety in an unfamiliar environment. Here, we verified impairment in axonal, but not somato-dendritic, localization of dex3 protein in cerebellar granule cells and demonstrated cellular and physiological phenotypes in postnatal cerebellum of CAPS2Δex3/Δex3 mice. Interestingly, both BDNF and NT-3 were markedly reduced in axons of cerebellar granule cells, resulting in a significant decrease in their release. As a result, dex3 mice showed developmental deficits in dendritic arborization of Purkinje cells, vermian lobulation and fissurization, and granule cell precursor proliferation. Paired-pulse facilitation at parallel fiber-Purkinje cell synapses was also impaired. Together, our results indicate that CAPS2 plays an important role in subcellular locality (axonal vs. somato-dendritic) of enhanced BDNF and NT-3 release, which is indispensable for proper development of postnatal cerebellum.
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan; JST/CREST, Kawaguchi, Saitama, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sadakata
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kakegawa
authors.affiliation: JST/CREST, Kawaguchi, Saitama, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Hosono
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Katoh-Semba
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Saruta
authors.affiliation: Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Ishizaki
authors.affiliation: Department of Physiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.affiliation: JST/CREST, Kawaguchi, Saitama, Japan; Biointerface Research group, Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Osaka, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
authors.affiliation: JST/CREST, Kawaguchi, Saitama, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000378:metabolism; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity; D020933:Neurotrophin 3 / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D013347:Subcellular Fractions / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C480975:CAPS2 protein, mouse; D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D020033:Protein Isoforms