Bidirectional alterations in cerebellar synaptic transmission of tottering and rolling Ca2+ channel mutant mice
Bidirectional alterations in cerebellar synaptic transmission of tottering and rolling Ca2+ channel mutant mice
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DOI：
10.1523/jneurosci.22-11-04388.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Imoto, K
中科院分区：
文献类型：
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作者：
Matsushita, K;Wakamori, M;Imoto, K
遗传性共济失调小鼠，摇摇欲坠(Tg)和滚动名古屋(Tg(Rol))，携带P/Q型钙通道α(1A)亚单位基因突变。突变的位置和神经表型是已知的，但突变如何导致症状以及不同突变如何导致不同的发病和严重程度的机制仍未解决。在这里，我们比较了野生型对照、TG和TG(Rol)小鼠小脑兴奋性突触传递的基本特性和其中钙通道亚型的作用。共济失调时，平行纤维-浦肯野细胞(PF-PC)突触的EPSC波幅显著降低。在幼年非共济失调的TG小鼠中，平行纤维介导的EPSC的幅值仅有轻微的降低，而在出生后28-35天的成年共济失调的TG小鼠中，其幅值却显著降低，表明PF-PC突触传递的损害与共济失调的表现有很好的相关性。而爬行纤维-浦肯野细胞(CF-PC)突触的EPSC波幅在TG中保持不变，在TG(Rol)中甚至升高，这与突触后谷氨酸受体的特性改变有关。在突变小鼠中，攀升纤维介导的EPSC更依赖于其他钙通道亚型，这表明这种代偿机制有助于维持CF-PC突触传递的基本完整。结果表明，P/Q型钙通道的不同突变不仅导致不同严重程度的初级效应，而且还导致不同的附加次级效应，导致平衡良好的神经网络的破坏。
Hereditary ataxic mice, tottering (tg) and rolling Nagoya (tg(rol)), carry mutations in the P/Q-type Ca2+ channel alpha(1A) subunit gene. The positions of the mutations and the neurological phenotypes are known, but the mechanisms of how the mutations cause the symptoms and how the different mutations lead to various onset and severity have remained unsolved. Here we compared fundamental properties of excitatory synaptic transmission in the cerebellum and roles of Ca2+ channel subtypes therein among wild-type control, tg, and tg(rol) mice. The amplitude of EPSC of the parallel fiber-Purkinje cell (PF-PC) synapses was considerably reduced in ataxic tg(rol). Although the amplitude of the parallel fiber-mediated EPSC was only mildly decreased in young non-ataxic tg mice, it was drastically diminished in adult ataxic tg mice of postnatal day 28-35, showing a good correlation between the impairment of the PF-PC synaptic transmission and manifestation of ataxia. In contrast, the EPSC amplitude of the climbing fiber-Purkinje cell (CF-PC) synapses was preserved in tg, and it was even increased in tg(rol), which was associated with altered properties of the postsynaptic glutamate receptors. The climbing fiber-mediated EPSC was more dependent on other Ca2+ channel subtypes in mutant mice, suggesting that such compensatory mechanisms contribute to maintaining the CF-PC synaptic transmission virtually intact. The results indicate that different mutations of the P/Q-type Ca2+ channel not only cause the primary effect of different severity but also lead to diverse additional secondary effects, resulting in disruption of well balanced neural networks.