Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release
Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release
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DOI：
10.1523/jneurosci.2279-06.2007
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发表时间：
2007-03-07
影响因子：
5.3
通讯作者：
Furuichi, Teiichi
中科院分区：
文献类型：
--
作者：
Sadakata, Tetsushi;Kakegawa, Wataru;Furuichi, Teiichi
Ca2(+)依赖的分泌激活蛋白2(CAPS2/CADPS2)是一种分泌颗粒相关蛋白，大量存在于小鼠小脑颗粒细胞的平行纤维终末，参与小脑发育所必需的神经营养因子-3(NT-3)和脑源性神经营养因子(BDNF)的释放。7号染色体上的人类同源基因位于自闭症的易感基因1中，自闭症是一种以几种小脑形态异常为特征的疾病。在此，我们报道CAPS2基因敲除小鼠缺乏NT-3和BDNF的释放，因此它们在小脑中表现出Trk受体的磷酸化抑制；这些小鼠在小脑发育和功能方面表现出明显的损害，包括神经元存活、有丝分裂后颗粒细胞的分化和迁移、浦肯野细胞的树突发生、小叶VI和VII之间的分叶、平行纤维-浦肯野细胞突触的结构和囊泡分布、平行纤维-浦肯野细胞突触的成对脉冲促进、Rotarod运动协调以及视动训练中的眼动可塑性。小脑外颗粒层颗粒细胞死亡增加见于小叶VI-VII和IX，其中高水平的BDNF和NT-3在小脑发育过程中有特异性的定位。因此，CAPS2的缺失表明，CAPS2介导的神经营养因子的释放对于小脑的正常发育和功能是必不可少的，包括神经元的分化和存活、形态发生、突触功能和运动学习/控制。本文还讨论了CAPS2基因与自闭症患者小脑功能障碍的关系。
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.