LONG TERM POTENTIATION AND DEPRESSION IN THE CEREBELLUM

描述(改编自申请人的摘要)：指导假设 神经生物学一直认为，在大脑中存储信息涉及到 持续性，使用突触强度的依赖变化。一件有用的事 这一努力的模型系统一直是小脑长期抑郁症 (LTD)，其中爬升光纤和平行光纤输入的共同激活 浦肯野神经元(PN)引起持续性的输入性抑制。 平行纤维PN突触。这一现象被认为是 对某些形式的运动学习是必要的，包括联想眼 前庭眼球反射的瞬目调节和适应。最近， 相反的现象，小脑长时程增强(LTP)也有 其中平行纤维PN突触通过 中频重复平行纤维刺激，因此 赋予该突触依赖使用的双向能力 修改，这是一个计算上重要的性质。近几年来，这 实验室专注于定义LTD入职的要求 使用平行纤维刺激的细胞培养模型系统 被谷氨酸脉冲和攀登纤维刺激取代为 PN的直接去极化。最近，我们开发了几个 扩展了我们可能解决的问题类型的新协议： 持续记录培养中的单个PNS以调查晚期 LTD的阶段；来自两个超减少的PN制剂的记录 LTD无树突棘室(急性分离的PNS) 和PN树突大片)；小脑LTP和LTD研究 颗粒细胞培养中的Pn对。此外，我们现在承诺 使用脑片制备的常规LTD实验。我们建议 使用这些技术来解决以下问题。首先，是 小脑有限公司，我们知道它是在突触后表达的，由 AMPA受体动力学的改变？第二，哪个细胞内 信号通路被小脑功能障碍晚期所激活吗？第三, 在颗粒细胞诱导LTP的要求是什么？ 浦肯野细胞突触及其表达部位在哪里？最后， 重新审视一个持续的争议，一氧化氮/cGMP的作用是什么？ 小脑LTD诱导中的信号传递？在基础科学的层面上，这些 研究是理解细胞底物的核心。 大脑区域中的信息存储，在该区域中， 投入和产出的定义异常明确。此外，这些 研究不仅对小脑有潜在的临床意义 运动障碍，也适用于一般的学习记忆障碍。

DESCRIPTION (Adapted from applicant's abstract): A guiding assumption in neurobiology has been that storage of information in the brain involves persistent, use dependent alterations in synaptic strength. One useful model system for this endeavor has been cerebellar long-term depression (LTD), in which co-activation of climbing fiber and parallel fiber inputs to a Purkinje neuron (PN), induces a persistent input specific depression of the parallel fiber PN synapse. This phenomenon has been suggested to be necessary for certain forms of motor learning including associative eye blink conditioning and adaptation of the vestibulo ocular reflex. Recently, the converse phenomenon, cerebellar long-term potentiation (LTP) has also been described, in which the parallel fiber PN synapse is strengthened by repetitive parallel fiber stimulation at intermediate frequencies, thus endowing this synapse with the capacity for use dependent bidirectional modification, a computationally important property. In recent years, this laboratory has focused upon defining the requirements for LTD induction using a cell culture model system in which parallel fiber stimulation is replaced by glutamate pulses and climbing fiber stimulation is replaced by direct depolarization of the PN. Most recently, we have developed several new protocols which have expanded the types of questions we may address: sustained recordings from single PNs in culture to investigate the late phase of LTD; recordings from two ultra reduced PN preparations that display LTD in the absence of dendritic spine compartments (acutely dissociated PNs and PN dendritic macropatches); and investigations of cerebellar LTP and LTD in granule cell PN pairs in culture. In addition, we now undertake "conventional" LTD experiments using a brain slice preparation. We propose to use these techniques to address the following questions. First, is cerebellar LTD, which we know to be expressed postsynaptically, mediated by an alteration in AMPA receptor kinetics? Second, which intracellular signaling pathways are engaged by the late phase of cerebellar LTD? Third, what are the requirements for the induction of LTP at the granule cell Purkinje cell synapse and where is its locus of expression? Finally, revisiting an ongoing controversy, what is the role of nitric oxide/cGMP signaling in cerebellar LTD induction? At the level of basic science, these investigations are central to an understanding of the cellular substrates of information storage in a brain area where the behavioral relevance of the inputs and outputs is unusually well defined. In addition, these investigations have potential clinical relevance not only for cerebellar motor disorders, but also for disorders of learning and memory generally.