Molecular mechanisms of long-term Depression in the hippocampus

突触可塑性是突触可以改变其传递效率的过程;两种主要形式是长时程增强（LTP）和长时程抑制（LTD）。脑中的主要兴奋性神经递质L-谷氨酸通过三种类型的离子型受体（以激动剂N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和红藻氨酸命名）以及G蛋白偶联的代谢型谷氨酸受体（mGluR）家族发挥其生理作用。自从发现NMDA受体（NMDARs）是海马CA 1区突触LTP的触发因子，并参与海马依赖性学习和记忆以来，NMDAR-LTP（NMDAR-LTP）在多种认知过程中的重要作用已变得非常明显。最近，越来越多的证据表明LTD在各种形式的学习和记忆中的重要性，LTD是由NMDAR或mGluRs激活引发的。这些可塑性过程在整个生命过程中都至关重要，从发育过程中建立的联系到成年后的明确学习和记忆形式。人们越来越多地认识到，LTP和LTD的改变以各种方式导致各种神经和精神疾病，如痴呆症，癫痫，抑郁症和精神分裂症。我们和其他人最近在可塑性和疾病之间建立了分子联系，这表明突触可塑性的失调可能直接导致许多神经病理学的病因。例如，在研究海马中LTD机制的过程中，我们最近发现了许多与神经病理学相关的蛋白质的关键作用，包括糖原合成酶激酶-3 β（GSK-3 β）。我们现在计划解决几个关键的未回答的问题，在海马NMDAR-LTD和mGluR-LTD的分子机制，重点是磷酸化级联，Ca 2+信号和谷氨酸受体贩运。基于广泛的试点数据，我们计划建立新的组件的分子途径的基础上不同形式的LTD，并精确地推断如何诱导LTD，以及伴随的胞质Ca 2+的瞬时增加，导致谷氨酸受体的突触表达的改变。我们工作的一个关键新进展将是在成年小鼠体内研究LTD。我们计划建立如何在简化的准备工作中已确定的信号级联在完整的动物。这些发现将有助于更全面地了解大脑中突触可塑性主要形式的分子基础，这项工作与大量主要的大脑疾病直接相关。

Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, exerts its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus, and that they are involved in hippocampus-dependent learning and memory, it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. We and others have recently made molecular links between plasticity and disease, which suggests that dysregulation in synaptic plasticity may directly contribute to the aetiology of a number of neurological pathologies. For example, in the process of studying mechanisms of LTD in the hippocampus, we have recently identified key roles for a number of proteins that are linked to neuropathogies, including glycogen synthase kinase-3beta (GSK-3beta). We now plan to address several key unanswered questions concerning molecular mechanisms of NMDAR-LTD and mGluR-LTD in the hippocampus, with a focus on phosphorylation cascades, Ca2+ signalling and glutamate receptor trafficking. Based on extensive pilot data we plan to establish new components of molecular pathways underlying different forms of LTD, and to deduce precisely how induction of LTD, and the accompanying transient increase in cytosolic Ca2+, results in alterations in the synaptic expression of glutamate receptors. A key new development for our work will be the study of LTD in adult mice in vivo. We plan to establish how the signalling cascades that have been identified in simplified preparations operate in the intact animal. These findings will contribute to a fuller understanding of the molecular basis of major forms of synaptic plasticity in the brain, work that is directly relevant to a substantial number of major brain disorders