TY - JOUR
T1 - Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release
AU - Sadakata, Tetsushi
AU - Kakegawa, Wataru
AU - Mizoguchi, Akira
AU - Washida, Miwa
AU - Katoh-Semba, Ritsuko
AU - Shutoh, Fumihiro
AU - Okamoto, Takehito
AU - Nakashima, Hisako
AU - Kimura, Kazushi
AU - Tanaka, Mika
AU - Sekine, Yukiko
AU - Itohara, Shigeyoshi
AU - Yuzaki, Michisuke
AU - Nagao, Soichi
AU - Furuichi, Teiichi
PY - 2007/3/7
Y1 - 2007/3/7
N2 - 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.
AB - 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.
KW - BDNF
KW - CAPS1/CADPS1
KW - CAPS2/CADPS2
KW - Cerebellum
KW - NT-3
KW - Neurotrophin
UR - http://www.scopus.com/inward/record.url?scp=33847784737&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847784737&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2279-06.2007
DO - 10.1523/JNEUROSCI.2279-06.2007
M3 - Article
C2 - 17344385
AN - SCOPUS:33847784737
VL - 27
SP - 2472
EP - 2482
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 10
ER -