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.

突触可塑性是突触时传输效率的长期变化，并且一直是学习和记忆的候选细胞机制。 Purkinje细胞是从小脑皮层发送输出的唯一神经元，显示出几种类型的突触可塑性。一种是兴奋性突触时的长期抑郁症，另一个是抑制性突触的反弹增强，这被认为是运动学习的基本机制。在这项研究中，我们一直在努力阐明突触可塑性的诱导，维持和调节的分子机制，并阐明其在小脑中信息处理和控制动物行为方面的作用。在抑制性突触下，我们发现了突触可塑性的新调节机制：突触活性抑制了反弹潜力的诱导。我们还阐明了该调节的分子机制。在兴奋性突触下，我们发现钙调蛋白依赖钙依赖性磷酸酶在诱导长期抑郁症的后期诱导中实施。此外，我们还研究了缺乏离子谷氨酸受体δ2亚基的突变小鼠的行为，该亚基在Purkinje细胞上选择性地表达在兴奋性突触上，对于诱导长期抑郁症是必不可少的。我们表明，突变小鼠未能对反射眼运动进行自适应修饰，这是运动学习的模型。我们还表明，突变小鼠的运动控制能力比Lurcher突变小鼠的运动能力更严重，后者在发育过程中丧失了所有Purkinje细胞。我们分析了几种运动不便的原因，并证明Δ2亚基缺乏通过增强攀岩纤维输入，导致盈余运动和影响运动控制范围比根本没有信号更糟，从而产生Purkinje细胞中的振荡活性。