Airaksinen M S, Eilers J, Garaschuk O, Thoenen H, Konnerth A, Meyer M
Department of Neurochemistry, Max Planck Institute for Psychiatry, Martinsried, Germany.
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1488-93. doi: 10.1073/pnas.94.4.1488.
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.
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，钙结合蛋白可能通过作为钙缓冲剂的作用来调节各种神经元特性。然而，钙结合蛋白在完整的整合系统中对神经系统功能的重要性尚不清楚。为了研究一种主要的内源性钙结合蛋白——钙结合蛋白D28k（钙结合蛋白）在体内的生理作用，我们通过基因靶向技术培育出了钙结合蛋白基因敲除突变小鼠。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，也不影响光镜水平下神经系统的结构。然而，基因敲除突变小鼠在运动协调测试中严重受损，提示小脑通路存在功能缺陷。浦肯野神经元是小脑皮质的唯一传出神经元，而橄榄下核神经元是攀缘纤维传入的来源，先前已证明它们表达钙结合蛋白。与这种不寻常的共济失调类型相关的是，小脑切片中浦肯野细胞的共聚焦钙成像显示，突触诱发的突触后钙瞬变有明显变化。在基因敲除突变小鼠中，其快速衰减成分（而非缓慢衰减成分）的幅度比野生型小鼠更大。我们得出结论，内源性钙结合蛋白对整合神经系统功能至关重要。
