Molecular basis of motor learning dependent on the cerebellum

突触可塑性是突触传递效能的长期改变，是学习和记忆的一种候选细胞机制。浦肯野细胞，一种从小脑皮层发送输出信号的单一神经元，显示出几种类型的突触可塑性。一种是兴奋性突触的长期抑制，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、维持和调控的分子机制，并阐明其在调节小脑信息加工和控制动物行为中的作用。在抑制性突触，我们发现了新的突触可塑性调节机制：突触活动抑制反弹增强的诱导。并阐明了该调控的分子机制。在兴奋性突触，我们发现钙依赖性磷酸酶钙调磷酸酶与长期抑郁的后期诱导有关。此外，我们还研究了缺乏嗜离子性谷氨酸受体δ 2亚基的突变小鼠的行为，该亚基在浦肯野细胞的兴奋性突触上选择性表达，是诱导长期抑郁所必需的。我们发现突变小鼠无法进行眼球反射运动的适应性修改，而眼球反射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受损比lurcher突变小鼠更严重，后者在发育过程中失去了所有浦肯野细胞。我们分析了严重运动失调的原因，并证明δ2亚基缺乏通过增强攀爬纤维输入来产生浦肯野细胞的振荡活动，导致运动过剩，对运动控制的影响比完全没有信号更严重。

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.