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率的长期改变，并且一直是学习和记忆的候选细胞机制，浦肯野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。兴奋性突触的抑制和抑制性突触的反弹增强被认为是运动学习的基本机制。在这项研究中，我们一直试图阐明其分子机制。突触可塑性的诱导、维持和调节，并阐明其在小脑信息处理调节和动物行为控制中的作用。在抑制性突触中，我们发现了突触可塑性的新调节机制：突触活动抑制。我们还阐明了这种调节的分子机制，我们发现钙依赖磷酸酶与诱导有关。此外，我们还研究了缺乏离子型谷氨酸受体δ 2 亚基的突变小鼠的行为，该亚基选择性地表达在浦肯野细胞的兴奋性突触上，对于诱导长期抑郁症是必需的。我们发现，突变小鼠无法对反射性眼球运动进行适应性修改，这是运动学习的模型。我们还发现，突变小鼠的运动控制能力比 lucher 突变小鼠受损更严重。我们分析了发育过程中所有浦肯野细胞的严重运动失调的原因，并证明δ2亚基缺陷通过增强攀爬纤维输入而产生浦肯野细胞的振荡活动，导致运动过剩并影响运动控制，这比没有信号更严重。。