突触的可塑性与学习,记忆机制

位于哺乳动物海马、小脑皮层的不同类型的可塑性突触,分别具有突触传递的长时程强化(LTP)或抑制(LTD)现象,它们可能是某些经典条件反射形成的基础。以LTD型突触为记忆装置的小脑局部神经网络,具有典型的适应控制能力。突触可塑性的另一类表现是突触前纤维长芽,有证据表明,伴随大脑—红核系统条件反射的建立,在红核神经元胞体附近有新的突触形成,这可能是长期记忆的基础。     

降钙素基因相关肽在突触可塑性调控和情绪记忆中的作用

降钙素基因相关肽(calcitonin gene-related peptide, CGRP)是由降钙素基因表达的一种神经肽类物质,分为α和β两种亚型。CGRP在人体内广泛分布,在外周和中枢神经系统中高表达。研究表明CGRP参与多种生理和病理生理活动,包括伤害性感觉信号的形成与传导、心血管功能的调节作用等。近年来越来越多的研究表明,在中枢神经系统中CGRP参与突触可塑性调控,并与认知和学习记忆功能密切相关。本文综述了CGRP在突触可塑性调控和情绪记忆中的作用研究进展,以期为临床治疗相关神经系统疾病提供新的分子靶点和理论依据。     

谷氨酸转运体能引发突触前离子流

谷氨酸转运体的功能是在递质出胞释放后清除突触间隙的递质 ,但转运体也携带离子。已证实在突触后膜和胶质细胞 ,转运体的激活可导致离子流的产生。某些谷氨酸转运体也存在于突触前终末 ,它们的活动可能影响突触前膜的电位 ,从而调节递质释放。但是 ,突触前终末的体积极小 ,在这些部位记录转运体介导的电流是一件较难的事情。最近 ,Palmer等通过记录两种大型的突触前终末 ,证实了谷氨酸转运体的确能引发突触前离子流。研究者记录了金鱼视网膜双极细胞的大型终末 ,发现突触前离子流与谷氨酸的释放相伴发生 ,这一离子流有较大的电导系数 ,且…     

NMDA受体参与小鼠的前额扣带回的神经突触传递

谷氨酸性突触是哺乳动物神经系统的主要兴奋性突触。在正常条件下,大多数的突触反应是由谷氨酸的AMPA受体传递的。NMDA受体在静息电位下为镁离子抑制。在被激活时,NMDA受体主要参与突触的可塑性变化。但是,许多NMDA受体拮抗剂在全身或局部注射时能产生行为效应,提示NMDA受体可能参与静息状态的生理功能。此文中,我们在离体的前额扣带回脑片上进行电生理记录,发现NMDA受体参与前额扣带回的突触传递。在重复刺激或近于生理性温度时,NMDA受体传递的反应更为明显。本文直接显示了NMDA受体参与前额扣带回的突触传递,并提示NMDA受体在前额扣带回中起着调节神经元兴奋的重要作用。     

代谢型谷氨酸受体在突触可塑性中的作用

突触可塑性是近几年神经科学研究的热点之一,因为它对于理解神经系统的学习、学习和记忆、多咱神经疾病等许多过程有着重要的意义。除了离子型谷氨酸受体外,代谢型谷氨酸受体也参与了一些脑区中不同形式的突触可塑性变化。本文就代谢型谷氨酸受体选择性激动剂和拮抗剂对长时程增强和长时程抑制的作用进行了综述,以助于人们进一步理解突触可塑性的细胞和分子机制。     

病毒突触的分子机制

人类嗜T细胞病毒I型(HTLV-1)和人类免疫缺陷病毒(HIV)感染CD4 T细胞后,已感染细胞通过病毒突触(virologicalsynapse)的方式与其他未感染的T细胞接触,将病毒颗粒直接传递到未感染细胞体内。这一新近发现的逆转录病毒感染方式涉及连续发生的一系列分子识别事件。目前对于病毒突触形成过程的分子识别机制尚无定论,但可以肯定的是,对其分子细节的深入研究必定会为人类攻克病毒性疾病提供新的思路。     

代谢型谷氨酸受体在突触可塑性中的作用研究进展

突触可塑性是近 30年来神经科学领域的研究热点之一 ,它主要包括长时程增强 (long termpotentiation ,LTP)和长时程抑制 (long termdepression ,LTD)。以往的研究已经证实 ,离子型谷氨酸受体 (iGluRs)中的NMDA受体和AMPA受体 ,在LTP和LTD的诱导和维持中通过阳离子内流 ,引起细胞内的级联反应而起作用。新近的研究发现 ,代谢型谷氨酸受体 (mGluRs)与G蛋白偶联 ,通过细胞内的多种信使系统介导慢突触传递。本文主要就mGluRs在不同脑区LTP和LTD中的作用进行综述     

突触体上谷氨酸递质的释放和检测

中枢兴奋性神经递质谷氨酸(Glu)从突触前的释放,是 Glu 神经传导的重要部分,也是造成兴奋性神经毒性的重要环节.在许多 Glu 释放的分析检测技术中,最近发展的 Glu 连续荧光分析法有许多优点.此法快速而灵敏度高,可对 Glu 释放作动态的检测.该法所揭示的 Glu 释放动力学表明:Glu 的胞泌释放,主要依赖于胞外Ca²⁺的内流,其释放呈两相性,对 ATP 有严格要求.Glu 的代谢异常和过量释放会对突触后受体造成滥刺激而导致神经毒性.研究对这种神经毒性的拮抗是目前神经科学的重要内容之一.Glu 连续荧光分析法为这类研究提供了一个有力手段.此法简便,易于在国内大多数实验室中进行.     

伏衬蛋白与学习记忆的突触机制

伏衬蛋白是一种多肽聚合体,广泛存在于多种动物细胞内,在胞浆外层和质膜内侧形成一层“衬里”,并在神经元和突触后致密物质内高度浓集。80年代以来,人们对这种蛋白质的生化特性、种间分布、细胞分布以及功能作用进行了不少研究。本文对有关资料作一简要的评述,并重点介绍这种蛋白质在学习记忆突触机制中的可能作用。     

From songs to synapses: molecular mechanisms of birdsong memory. Molecular mechanisms of auditory learning in songbirds involve immediate early genes, including zenk and arc, the ERK/MAPK pathway and synapsins

There are remarkable behavioral, neural, and genetic similarities between the way songbirds learn to sing and human infants learn to speak. Furthermore, the brain regions involved in birdsong learning, perception, and production have been identified and characterized in detail. In particular, the caudal medial nidopallium (the avian analog of the mammalian auditory-association cortex) has been found to contain the neural substrate of auditory memory, paving the way for analyses of the underlying molecular mechanisms. Recently, the zebra finch genome was sequenced, and annotated cDNA databases representing over 15,000 unique brain-expressed genes are available, enabling high-throughput gene expression analyses. Here we review the involvement of immediate early genes (e.g. zenk and arc), their downstream targets (e.g. synapsins), and their regulatory signaling pathways (e.g. MAPK/ERK) in songbird memory. We propose that in-depth investigations of zenk- and ERK-dependent cascades will help to further unravel the molecular basis of auditory memory.     

Sleep is required to consolidate odor memory and remodel olfactory synapses

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Time-dependent and selective microglia-mediated removal of spinal synapses in neuropathic pain

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Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses.

The protein brain-derived neurotrophic factor (BDNF) has been postulated to be a retrograde or paracrine synaptic messenger in long-term potentiation and other forms of activity-dependent synaptic plasticity. Although crucial for this concept, direct evidence for the activity-dependent synaptic release of BDNF is lacking. Here we investigate secretion of BDNF labelled with green fluorescent protein (BDNF-GFP) by monitoring the changes in fluorescence intensity of dendritic BDNF-GFP vesicles at glutamatergic synaptic junctions of living hippocampal neurons. We show that high-frequency activation of glutamatergic synapses triggers the release of BDNF-GFP from synaptically localized secretory granules. This release depends on activation of postsynaptic ionotropic glutamate receptors and on postsynaptic Ca(2+) influx. Release of BDNF-GFP is also observed from extrasynaptic dendritic vesicle clusters, suggesting that a possible spatial restriction of BDNF release to specific synaptic sites can only occur if the postsynaptic depolarization remains local. These results support the concept of BDNF being a synaptic messenger of activity-dependent synaptic plasticity, which is released from postsynaptic neurons.     

Common molecular mechanisms in explicit and implicit memory

Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. In this review, we focus on recent advances in our understanding of two types of memory storage: (i) sensitization in Aplysia, a simple form of implicit memory, and (ii) formation of explicit spatial memories in the mouse hippocampus. These two processes share common molecular mechanisms that have been highly conserved through evolution.     

The molecular biology of memory storage: a dialog between genes and synapses

The biology of learning, and short-term and long-term memory, as revealed by Aplysia and other organisms, is reviewed.     

Understanding the physical basis of memory: Molecular mechanisms of the engram

Memory, defined as the storage and use of learned information in the brain, is necessary to modulate behavior and critical for animals to adapt to their environments and survive. Despite being a cornerstone of brain function, questions surrounding the molecular and cellular mechanisms of how information is encoded, stored, and recalled remain largely unanswered. One widely held theory is that an engram is formed by a group of neurons that are active during learning, which undergoes biochemical and physical changes to store information in a stable state, and that are later reactivated during recall of the memory. In the past decade, the development of engram labeling methodologies has proven useful to investigate the biology of memory at the molecular and cellular levels. Engram technology allows the study of individual memories associated with particular experiences and their evolution over time, with enough experimental resolution to discriminate between different memory processes: learning (encoding), consolidation (the passage from short-term to long-term memories), and storage (the maintenance of memory in the brain). Here, we review the current understanding of memory formation at a molecular and cellular level by focusing on insights provided using engram technology.     

Gephyrin expression and clustering affects the size of glutamatergic synaptic contacts

We have recently shown that disrupting the expression and post-synaptic clustering of gephyrin in cultured hippocampal pyramidal cells, by either gephyrin RNAi (RNA interference) or over-expression of a dominant negative gephyrin-enhanced green fluorescent protein (EGFP) fusion protein, leads to decreased number of post-synaptic gephyrin and GABA_A receptor clusters and to reduced GABAergic innervation of these cells. On the other hand, increasing gephyrin expression led to a small increase in the number of gephyrin and GABA_A receptor clusters and to little or no effect on GABAergic innervation. We are now reporting that altering gephyrin expression and clustering affects the size but not the density of glutamatergic synaptic contacts. Knocking down gephyrin with gephyrin RNAi, or preventing gephyrin clustering by over-expression of the dominant negative gephyrin-enhanced green fluorescent protein fusion protein, leads to larger post-synaptic PSD-95 clusters and larger pre-synaptic glutamatergic terminals. On the other hand, over-expression of gephyrin leads to slightly smaller PSD-95 clusters and pre-synaptic glutamatergic terminals. The change in size of PSD-95 clusters were accompanied by a parallel change in the size of NR2-NMDA receptor clusters. It is concluded that the levels of expression and clustering of gephyrin, a protein that concentrates at the post-synaptic complex of the inhibitory synapses, not only has homotypic effects on GABAergic synaptic contacts, but also has heterotypic effects on glutamatergic synaptic contacts. We are proposing that gephyrin is a counterpart of the post-synaptic glutamatergic scaffold protein PSD-95 in regulating the number and/or size of the excitatory and inhibitory synaptic contacts.     

谷氨酸转运体与疼痛

中枢神经系统谷氨酸生理浓度主要依赖神经细胞和神经胶质细胞上谷氨酸转运体维持,谷氨酸转运体的功能紊乱会导致谷氨酸的累积。谷氨酸转运体在吗啡镇痛及耐受中扮演一定的角色,并在神经病理性痛中发挥重要作用。谷氨酸转运体可能作为治疗疼痛的一个潜在的药物靶点。