4.7 Article

CAPS1 Deficiency Perturbs Dense-Core Vesicle Trafficking and Golgi Structure and Reduces Presynaptic Release Probability in the Mouse Brain

期刊

JOURNAL OF NEUROSCIENCE
卷 33, 期 44, 页码 17326-17334

出版社

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2777-13.2013

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资金

  1. Japan Foundation for Neuroscience and Mental Health
  2. Uehara Memorial Foundation
  3. Takeda Science Foundation
  4. Nakajima Foundation
  5. Yamada Science Foundation
  6. Mother and Child Health Foundation
  7. NOVARTIS Foundation for the Promotion of Science
  8. Inamori Foundation, Scientific Research on Innovative Areas Foundation of Synapse and Neurocircuit Pathology,
  9. CREST
  10. FIRST program of the Japan Science and Technology Agency, Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [25110707]
  11. Japan Society for the Promotion of Science [25430061]
  12. Institute of Physical and Chemical Research (RIKEN Brain Science Institute)
  13. Grants-in-Aid for Scientific Research [23689012, 25110707, 25430061, 23300137, 23240062] Funding Source: KAKEN

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Ca2+-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.

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