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Molecular basis of motor learning dependent on the cerebellum

运动学习的分子基础依赖于小脑

基本信息

批准号：
12210011
负责人：
HIRANO Tomoo
金额：
$ 59.14万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

Synaptic plasticity is the long-lasting alteration of transmission efficacy at a synapse, and has been a candidate cellular mechanism for learning and memory. Purkinje cells, sole neurons sending outputs from the cerebellar cortex, show several types of synaptic plasticity. One is the long term depression at excitatory synapses and another is the rebound potentiation at inhibitory synapses, which have been regarded as basic mechanisms for motor learning. In this study, we have been trying to elucidate the molecular mechanisms of induction, maintenance and regulation of the synaptic plasticity, and also to clarify its roles in regulation of information processing in the cerebellum and in the control of animal behavior. At inhibitory synapses we discovered the novel regulation mechanism of synaptic plasticity: the synaptic activity suppresses the induction of rebound potentiation. We also clarified molecular mechanism of that regulation. At excitatory synapses we found that calcineurin, calcium-dependent phosphatase, is implicated in the induction of late phase of long term depression. Further, we have also studied the behavior of mutant mice deficient in the ionotropic glutamate receptor δ 2 subunit, which is selectively expressed at excitatory synapses on a Purkinje cell and is necessary for the induction of long term depression. We showed that the mutant mice failed to perform adaptive modifications of reflex eye movements, which are models of motor learning. We also showed that the motor control ability of the mutant mouse was impaired more severely than that of lurcher mutant mouse, which lose all Purkinje cells during development. We analyzed the cause of sever motor discoordination and demonstrated that the δ2 subunit deficiency produces the oscillating activity in Purkinje cells by enhancing climbing fiber inputs, causing surplus movement and affecting motor control worse than no signal at all.

突触可塑性是突触传递效能的长期改变，是学习和记忆的候选细胞机制。浦肯野细胞是唯一从小脑皮质发出输出的神经元，显示出几种类型的突触可塑性。一种是兴奋性突触的长时抑制，另一种是抑制性突触的反弹增强，它们被认为是运动学习的基本机制。在本研究中，我们试图阐明突触可塑性的诱导、维持和调节的分子机制，并阐明其在小脑信息处理和动物行为控制中的作用。在抑制性突触，我们发现了突触可塑性的新调节机制：突触活性抑制反弹增强的诱导。我们还阐明了该调控的分子机制。在兴奋性突触，我们发现钙调神经磷酸酶，钙依赖的磷酸酶，与诱导晚期的长期抑郁有关。此外，我们还研究了离子型谷氨酸受体δ2亚单位缺陷突变小鼠的行为，该亚单位选择性地表达在浦肯野细胞的兴奋性突触上，是诱导长期抑郁所必需的。我们发现，突变小鼠未能对反射性眼球运动进行适应性修改，而反射性眼球运动是运动学习的模型。我们还发现，突变小鼠的运动控制能力比Lurcher突变小鼠更严重，后者在发育过程中失去了所有的浦肯野细胞。我们分析了严重运动失调的原因，证明δ2亚单位缺陷通过增加攀爬纤维输入，导致多余的运动，并比完全没有信号更严重地影响运动控制，从而在浦肯野细胞中产生振荡活动。