突触可塑性与学习记忆

以LTP为例,通过综述前人实验及理论,对突触可塑性的两种表现形式:即结构可塑性和 传递效能可塑性与学习记忆的关系进行了研究.突触可塑性被认为是学习记忆的神经学基础,而其 中最受人们关注、研究最多的是突触传递的长时程增强(LTP).     

谷氨酸能神经传递系统研究进展

谷氨酸广布于大脑皮质等处,以(-酮戊二酸、谷氨酰胺或鸟氨酸等为前体进行合成,通过快突触传递或慢突触传递与突触后膜上的三种类型的受体相结合,参与学习记忆、突触可塑性、细胞凋亡、自主运动神经活动及神经毒性作用等生理和病理功能。     

谷氨酸能神经传递系统研究进展

谷氨酸广布于大脑皮质等处,以(-酮戊二酸、谷氨酰胺或鸟氨酸等为前体进行合成,通过快突触传递或慢突触传递与突触后膜上的三种类型的受体相结合,参与学习记忆、突触可塑性、细胞凋亡、自主运动神经活动及神经毒性作用等生理和病理功能.     

记忆研究方向的新探讨

本文介绍了神经心理学有关学习记忆的研究进展，认为突触可塑性（尤其是ＬＴＰ）与蛋白质分子作用结合起来是学习记忆的重要研究方向。     

铅对神经系统学习记忆功能的损伤及药物的修复机制

概述了中国科学技术大学神经毒理学实验室在铅对神经系统学习记忆功能的损伤及药物的修复机制方面的研究进展,主要包括:①铅对海马突触可塑性的影响;②铅影响离子通道的作用机制;③铅对NMDA受体、非NMDA受体及其通道特性的损伤;④铅与神经递质的相互作用;⑤铅影响基因对学习记忆的调控;⑥牛磺酸,神经节苷脂,抗氧化剂等药物对铅引起的学习记忆损伤的修复机制.     

PTPa基因敲除对小鼠海马CA1区突触可塑性的影响

通过PTPa基因敲除(knock out)小鼠来研究海马突触可塑性的变化,在海马schaffer collateral-CA1通路中采用场电位记录的方法研究发现,与Wild Type相比较,基因敲除小鼠的Long Term Potentiation(LTP)增强而Long Term Depression(LTD)受到抑制,去增强效应消失,θ频率诱导的LTP增强,但是其基本的突触传递性质并没有发生变化.     

PTPα基因敲除对小鼠海马CA1区突触可塑性的影响

通过PTPα基因敲除（knockout）小鼠来研究海马突触可塑性的变化，在海马schaffer collateral—CA1通路中采用场电位记录的方法研究发现，与Wild Type相比较，基因敲除小鼠的Long Term Potentiation（LTP）增强而Long Term Depression（LTD）受到抑制，去增强效应消失。θ频率诱导的LTP增强，但是其基本的突触传递性质并没有发生变化．     

基于双反相二维色谱串联质谱技术的大鼠海马膜蛋白分析

色谱与质谱联用技术在蛋白质组学研究中应用广泛,特别是二维色谱分离技术的发展,为复杂生物样品的分离分析提供了更为精准的技术手段.海马是大脑颞叶内侧的一个重要脑区,主要负责哺乳动物的学习和记忆,实现这些功能的生理过程与海马膜蛋白密切相关,但由于海马膜蛋白具有强疏水性和低丰度的特点,因此在分离和鉴定上难度较高.运用差速离心的方法分离纯化得到成年大鼠的海马膜蛋白,采用双反相二维色谱串联质谱技术进行分离分析.最终鉴定2 502个蛋白,结合生物信息学分析发现,所鉴定到的2 502个蛋白在包含蛋白定位、突触可塑性、蛋白运输以及囊泡转运等在内的与学习记忆功能密切相关的生理过程中均有涉及.这一分析结果为更加全面的揭示海马膜蛋白与脑海马区的特定功能间的具体关系提供了重要的参考.     

AMPA受体转运的调节与突触可塑性之间关系的研究进展

<正>AMPA受体介导大脑中绝大多数快兴奋性突触传递。突触可塑性即神经元突触效能的动态变化被认为是学习和记忆中信息编码和储存的基础。其中一个最重要的机制认为突触强度的调节与AMPA受体在突触中的转运调节密切相关。AMPA受体的生命周期包括生物合成、跨膜转运以及突触靶向性降解,都是受细胞内众多的细胞内调节蛋白     

衰老大鼠学习行为与海马突触相关蛋白表达的研究

研究衰老大鼠的学习行为与海马内突触相关蛋白的表达．运用Y-迷宫方法对幼年对照组（断乳期）和老年期（22月龄）雄性Sprague—Dawley大鼠进行Y-迷宫空间学习记忆行为训练,之后利用免疫组化和Western blot方法检测2组大鼠海马内突触素（synaptophysin,Syn）、生长相关蛋白（GAP-43）的表达情况．研究结果：（1）2组相比,老年组的学习能力较强,幼年对照组记忆能力较强（P〈0．05）;（2）生长相关蛋白GAP-43在老年组海马内的表达显著高于幼年对照组;而突触素的表达低于幼年对照组（P〈0．01）．提示,GAP-43和突触素可能参与大鼠空间分辨学习记忆的过程,老年大鼠的中枢神经系统保持着潜在的神经元退化修复的功能．     

Locally dynamic synaptic learning rules in pyramidal neuron dendrites

Long-term potentiation (LTP) of synaptic transmission underlies aspects of learning and memory. LTP is input-specific at the level of individual synapses, but neural network models predict interactions between plasticity at nearby synapses. Here we show in mouse hippocampal pyramidal cells that LTP at individual synapses reduces the threshold for potentiation at neighbouring synapses. After input-specific LTP induction by two-photon glutamate uncaging or by synaptic stimulation, subthreshold stimuli, which by themselves were too weak to trigger LTP, caused robust LTP and spine enlargement at neighbouring spines. Furthermore, LTP induction broadened the presynaptic-postsynaptic spike interval for spike-timing-dependent LTP within a dendritic neighbourhood. The reduction in the threshold for LTP induction lasted approximately 10 min and spread over approximately 10 microm of dendrite. These local interactions between neighbouring synapses support clustered plasticity models of memory storage and could allow for the binding of behaviourally linked information on the same dendritic branch.     

Genetic enhancement of learning and memory in mice.

Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.     

NMDA application potentiates synaptic transmission in the hippocampus

The NMDA (N-methyl-D-aspartate) class of glutamate receptor plays a critical role in a variety of forms of synaptic plasticity in the vertebrate central nervous system. One extensively studied example of plasticity is long-term potentiation (LTP), a remarkably long-lasting enhancement of synaptic efficiency induced in the hippocampus by brief, high-frequency stimulation of excitatory synapses. LTP is a strong candidate for a cellular mechanism of learning and memory. The site of LTP induction appears to be the postsynaptic cell and induction requires both activation of NMDA receptors by synaptically released glutamate and depolarization of the postsynaptic membrane. It is proposed that this depolarization relieves a voltage-dependent Mg2+ block of the NMDA receptor channel, resulting in increased calcium influx which is the trigger for the induction of LTP. This model predicts that application of a large depolarizing dose of NMDA should be sufficient to evoke LTP. In agreement with a previous study, we have found that NMDA or glutamate application does potentiate synaptic transmission in the hippocampus. This agonist-induced potentiation is, however, decremental and short-lived, unlike LTP. It is occluded shortly after the induction of LTP and a similar short-term potentiation can be evoked by synaptically released glutamate. We thus propose that LTP has two components, a short-term, decremental component which can be mimicked by NMDA receptor activation, and a long-lasting, non-decremental component which, in addition to requiring activation of NMDA receptors, requires stimulation of presynaptic afferents.     

Interaction with the NMDA receptor locks CaMKII in an active conformation.

Calcium- and calmodulin-dependent protein kinase II (CaMKII) and glutamate receptors are integrally involved in forms of synaptic plasticity that may underlie learning and memory. In the simplest model for long-term potentiation, CaMKII is activated by Ca2+ influx through NMDA (N-methyl-D-aspartate) receptors and then potentiates synaptic efficacy by inducing synaptic insertion and increased single-channel conductance of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Here we show that regulated CaMKII interaction with two sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons. This interaction can lead to additional forms of potentiation by: facilitated CaMKII response to synaptic Ca2+; suppression of inhibitory autophosphorylation of CaMKII; and, most notably, direct generation of sustained Ca2+/calmodulin (CaM)-independent (autonomous) kinase activity by a mechanism that is independent of the phosphorylation state. Furthermore, the interaction leads to trapping of CaM that may reduce down-regulation of NMDA receptor activity. CaMKII-NR2B interaction may be prototypical for direct activation of a kinase by its targeting protein.     

Recovery of spatial learning deficits after decay of electrically induced synaptic enhancement in the hippocampus

A widespread interest in a long-lasting form of synaptic enhancement in hippocampal circuits has arisen largely because it might reflect the activation of physiological mechanisms that underlie rapid associative learning. As its induction normally requires the 'Hebbian' association of activity on a number of input fibres, we refer to the process as long-term enhancement (LTE) rather than long-term potentiation (LTP), to emphasize its distinction from the ubiquitous, non-associative 'potentiation' phenomena that occur at most synapses, including those exhibiting LTE. Among other evidence that LTE might actually have a role in associative memory is the demonstration that repeated high-frequency stimulation, which saturated the inducible LTE, caused a severe deficit in spatial learning, although it had no effect on well established spatial memory. These results were consistent with a widespread view that information need only temporarily be stored in the hippocampal formation in order for long-term memories to be established in neocortical circuits. In this context, it is important to understand whether the possible underlying synaptic changes are of a permanent character, or are relatively transient. A second question is whether the actual cause of the observed learning deficit is the distruption of the synaptic weight distribution, and/or the limitation of further synaptic change, which presumably results from experimental saturation of the LTE mechanism. Alternatively, the deficit could be a consequence of some unobserved secondary effect of the high-frequency electrical stimulation. Here we demonstrate that learning capacity recovers in about the same time that it takes LTE to decay, which strongly favours the first possibility and supports the idea that LTE-like processes actually underlie associative memory.     

Structural basis of long-term potentiation in single dendritic spines

Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling that has been proposed to be a cellular basis of learning and memory. How structural remodelling supports synaptic plasticity, such as long-term potentiation, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.     

Clustering of L-type Ca2+ channels at the base of major dendrites in hippocampal pyramidal neurons

Integration and processing of electrical signals in individual neurons depend critically on the spatial distribution of ion channels on the cell surface. In hippocampal pyramidal neurons, voltage-sensitive calcium channels have important roles in the control of Ca2(+)-dependent cellular processes such as action potential generation, neurotransmitter release, and epileptogenesis. Long-term potentiation of synaptic transmission in the hippocampal pyramidal cell, a form of neuronal plasticity that is thought to represent a cellular correlate of learning and memory, is dependent on Ca2+ entry mediated by synaptic activation of glutamate receptors that have a high affinity for NMDA (N-methyl(-D-aspartate) and are located in distal dendrites. Stimuli causing long-term potentiation at these distal synapses also cause a large local increase in cytosolic Ca2+ in the proximal regions of dendrites. This increase has been proposed to result from activation of voltage-gated Ca2+ channels. At least four types of voltage-gated Ca2+ channels, designated N, L. T and P, may be involved in these processes. Here we show that L-type Ca2+ channels, visualized using a monoclonal antibody, are located in the cell bodies and proximal dendrites of hippocampal pyramidal cells and are clustered in high density at the base of major dendrites. We suggest that these high densities of L-type Ca2+ channels may serve to mediate Ca2+ entry into the pyramidal cell body and proximal dendrites in response to summed excitatory inputs to the distal dendrites and to initiate intracellular regulatory events in the cell body in response to the same synaptic inputs that cause long-term potentiation at distal dendritic synapses.