title: CAPS1 deficiency perturbs dense-core vesicle trafficking and Golgi structure and reduces presynaptic release probability in the mouse brain.
abstract: Ca(2+)-dependent activator protein for secretion 1 (CAPS1) plays a regulatory role in the dense-core vesicle (DCV) exocytosis pathway, but its functions at the cellular and synaptic levels in the brain are essentially unknown because of neonatal death soon after birth in Caps1 knock-out mice. To clarify the functions of the protein in the brain, we generated two conditional knock-out (cKO) mouse lines: 1) one lacking Caps1 in the forebrain; and 2) the other lacking Caps1 in the cerebellum. Both cKO mouse lines were born normally and grew to adulthood, although they showed subcellular and synaptic abnormalities. Forebrain-specific Caps1 cKO mice showed reduced immunoreactivity for the DCV marker secretogranin II (SgII) and the trans-Golgi network (TGN) marker syntaxin 6, a reduced number of presynaptic DCVs, and dilated trans-Golgi cisternae in the CA3 region. Cerebellum-specific Caps1 cKO mice had decreased immunoreactivity for SgII and brain-derived neurotrophic factor (BDNF) along the climbing fibers. At climbing fiber-Purkinje cell synapses, the number of DCVs was markedly lower and the number of synaptic vesicles was also reduced. Correspondingly, the mean amplitude of EPSCs was decreased, whereas paired-pulse depression was significantly increased. Our results suggest that loss of CAPS1 disrupts the TGN-DCV pathway, which possibly impairs synaptic transmission by reducing the presynaptic release probability.
authors.affiliation: Advanced Scientific Research Leaders Development Unit and Department of Molecular and Cellular Neurobiology, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan, Japan Science and Technology Agency/Core Research for Evolutional Science and Technology, Kawaguchi, Saitama 332-0012, Japan, Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan, Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan, Graduate School of Medical Science, Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan, Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan, Laboratory for Behavioral Genetics, Funding Program for World-Leading Innovative R&D on Science and Technology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, Department of Developmental Genetics, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan, and Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sadakata
authors.forename: Wataru
authors.initials: W
authors.lastname: Kakegawa
authors.forename: Yo
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Mayu
authors.initials: M
authors.lastname: Hosono
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Katoh-Semba
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekine
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sato
authors.forename: Mika
authors.initials: M
authors.lastname: Tanaka
authors.forename: Takuji
authors.initials: T
authors.lastname: Iwasato
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Furuyama
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Ishizaki
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.forename: Teiichi
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002135:Calcium-Binding Proteins / Q000172:deficiency*; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D011336:Probability; D021381:Protein Transport / Q000235:genetics; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: C510820:Cadps protein, mouse; D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins