Ataxia and altered dendritic calcium signaling in mice carrying a targeted null mutation of the calbindin D28k gene
Ataxia and altered dendritic calcium signaling in mice carrying a targeted null mutation of the calbindin D28k gene
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DOI：
10.1073/pnas.94.4.1488
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发表时间：
1997-02-18
影响因子：
11.1
通讯作者：
Meyer, M
中科院分区：
文献类型：
--
作者：
Airaksinen, MS;Eilers, J;Meyer, M
细胞内钙结合蛋白在许多神经元群体中大量表达。先前的证据表明，钙结合蛋白可以调节各种神经元特性，可能是通过它们作为钙缓冲液的作用。为了研究一种主要的内源性钙结合蛋白calbindin D28k （calbindin）在体内的生理作用，我们通过基因靶向产生了calbindin零突变小鼠。令人惊讶的是，钙结合蛋白缺乏并不影响发育和行为的一般参数或光微观水平的神经系统结构。然而，零突变体在运动协调测试中严重受损，提示小脑通路的功能缺陷。浦肯野神经元是小脑皮层唯一的传出神经，而下橄榄神经元是攀爬纤维传入神经的来源，先前已被证明表达calbindin，与这种不寻常的共济失调相关，小脑片浦肯野细胞的共聚焦钙成像显示突触诱发的突触后钙瞬间的显著变化。它们的快速而非慢速衰变成分在零突变体中比在野生型小鼠中具有更大的振幅。我们认为内源性钙结合蛋白对综合神经系统的功能至关重要。
Intracellular calcium-binding proteins are abundantly expressed in many neuronal populations. Previous evidence suggests that calcium-binding proteins can modulate various neuronal properties, presumably by their action as calcium buffers. The importance of calcium-binding proteins for nervous system function in an intact integrated system is, however, less clear, To investigate the physiological role of a major endogenous calcium-binding protein, calbindin D28k (calbindin) in vivo, we have generated calbindin null mutant mice by gene targeting. Surprisingly, calbindin deficiency does not affect general parameters of development and behavior or the structure of the nervous system at the light microscopic level. Null mutants are, however, severely impaired in tests of motor coordination, suggesting functional deficits in cerebellar pathways. Purkinje neurons, the only efferent of the cerebellar cortex, and inferior olive neurons, the source of the climbing fiber afferent, have previously been shown to express calbindin, Correlated with this unusual type of ataxia, confocal calcium imaging of Purkinje cells in cerebellar slices revealed marked changes of synaptically evoked postsynaptic calcium transients. Their fast, but not their slow, decay component had larger amplitudes in null mutant than in wild-type mice. We conclude that endogenous calbindin is of crucial importance for integrated nervous system function.