Ogasawara Hideaki, Doi Tomokazu, Kawato Mitsuo
National Institute of Information and Communications Technology, Kyoto, Japan.
Neurosignals. 2008;16(4):300-17. doi: 10.1159/000123040. Epub 2008 Jul 18.
Long-term depression (LTD) at parallel fiber-Purkinje cell (PF-PC) synapses is thought to be the cellular correlate of cerebellar associative learning. The molecular processes are, in brief, phosphorylation of AMPA-type glutamate receptors (AMPARs) and their subsequent removal from the surface of the PF-PC synapse. In order to elucidate the fundamental mechanisms for cerebellar LTD and further the understanding of its computational role, we have investigated its systems biology and proposed the following hypotheses, some of which have already been experimentally verified: (1) due to the mitogen-activated protein kinase (MAPK)-protein kinase C (PKC) positive feedback loop, phosphorylation of AMPARs is an all-or-none event; (2) the inositol 1,4,5-triphosphate receptor detects concurrent PF and climbing fiber inputs, forming the cellular basis for associative learning, and (3) the local concentration of nitric oxide in the PC dendrite reflects the relevance of a given context, enabling context-dependent selection of learning modules within the cerebellum. In this review, we first introduce theoretical studies on cerebellar LTD, mainly focusing on our own published work, followed by a discussion of the effects of stochasticity, localization, diffusion, and scaffolding. Neurons embody two features that are apparently contradictory, yet necessary for synaptic memory: stability and plasticity. We will also present models for explaining how neurons solve this dilemma. In the final section, we propose a conceptual model in which a cascade of excitable dynamics with different time scales, i.e., Ca(2+)-induced Ca(2+) release, the MAPK-PKC positive feedback loop, and protein kinase Mzeta (PKMzeta)-induced PKMzeta synthesis, provides a mechanism for stable memory that is still amenable to modifications.
平行纤维-浦肯野细胞（PF-PC）突触处的长时程抑制（LTD）被认为是小脑联合学习的细胞关联机制。简要来说，其分子过程是AMPA型谷氨酸受体（AMPARs）的磷酸化以及随后它们从PF-PC突触表面的移除。为了阐明小脑LTD的基本机制并进一步理解其计算作用，我们研究了其系统生物学并提出了以下假设，其中一些已经得到实验验证：（1）由于丝裂原活化蛋白激酶（MAPK）-蛋白激酶C（PKC）正反馈回路，AMPARs的磷酸化是一个全或无的事件；（2）肌醇1,4,5-三磷酸受体检测并行的PF和攀爬纤维输入，形成联合学习的细胞基础，以及（3）浦肯野细胞树突中一氧化氮的局部浓度反映了给定情境的相关性，使得能够在小脑中进行依赖情境的学习模块选择。在这篇综述中，我们首先介绍关于小脑LTD的理论研究，主要聚焦于我们自己已发表的工作，随后讨论随机性、定位、扩散和支架作用的影响。神经元体现出两个看似矛盾但对于突触记忆又是必需的特征：稳定性和可塑性。我们还将展示用于解释神经元如何解决这一困境的模型。在最后一部分，我们提出一个概念模型，其中一系列具有不同时间尺度的兴奋性动力学，即钙诱导的钙释放、MAPK-PKC正反馈回路以及蛋白激酶Mζ（PKMzeta）诱导的PKMzeta合成，提供了一种稳定记忆的机制，这种机制仍然易于修改。
