长时程突触可塑性中的突触标识

神经元长时程突触可塑性是学习和记忆的基础,神经元长时程突触可塑性的维持依赖于基因的转录和蛋白质合成.然而,这些转录产物和新合成的蛋白质是如何从胞体运输到突触点,还不甚清楚.近年来的研究显示,当长时程突触可塑性发生时,被激活的突触能通过建立突触标记(synaptic tag)来识别、捕捉和利用其所需要的基因产物,以维持突触可塑性的长时程变化.这一过程或现象被称为突触标识(synaptic tagging).本文就近年来突触标识的研究进展作一概述.     

Synaptic transmission and plasticity in the amygdala

Numerous studies in both rats and humans indicate the importance of the amygdala in the acquisition and expression of learned fear. The identification of the amygdala as an essential neural substrate for fear conditioning has permitted neurophysiological examinations of synaptic processes in the amygdala that may mediate fear conditioning. One candidate cellular mechanism for fear conditioning is long-term potentiation (LTP), an enduring increase in synaptic transmission induced by high-frequency stimulation of excitatory afferents. At present, the mechanisms underlying the induction and expression of amygdaloid LTP are only beginning to be understood, and probably involve both theN-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subclasses of glutamate receptors. This article will examine recent studies of synaptic transmission and plasticity in the amygdala in an effort to understand the relationships of these processes to aversive learning and memory.     

The synaptic plasticity and memory hypothesis: encoding,storage and persistence

The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.     

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.     

神经元的突触可塑性与学习和记忆

大量研究表明,神经元的突触可塑性包括功能可塑性和结构可塑性,与学习和记忆密切相关.最近,在经过训练的动物海马区,记录到了学习诱导的长时程增强(long term potentiation,LTP),如果用激酶抑制剂阻断晚期LTP,就会使大鼠丧失训练形成的记忆.这些结果指出,LTP可能是形成记忆的分子基础.因此,进一步研究哺乳动物脑内突触可塑性的分子机制,对揭示学习和记忆的神经基础有重要意义.此外,在精神迟滞性疾病和神经退行性疾病患者脑内记录到异常的LTP,并发现神经元的树突棘数量减少,形态上产生畸变或萎缩,同时发现,产生突变的基因大多编码调节突触可塑性的信号通路蛋白,故突触可塑性研究也将促进精神和神经疾病的预防和治疗.综述了突触可塑性研究的最新进展,并展望了其发展前景.     

大鼠海马CA3区的习得性长时程突触增强

本实验应用慢性埋植电极技术以电生理学结合行为学的方法,观察大鼠条件性饮水反应的建立、消退和再建立过程中,其海马CA_3区突触效应的变化规律。以刺激内嗅区的穿通纤维(PP)诱发的单突触的群体锋电位(PS)及群体兴奋性突触后电位(EPSPs)为指标,经叠加处理分析,发现随着条件反应的建立,海马CA_3锥体细胞出现突触效应的长时程增强(LTP),它随行为反应的实验性消退而消退,而在随后再次建立条件反应时,又重新出现;且无论此LTP达最高水平还是它的完全消退均超前于条件性行为反应的水平。又在一个实验日训练作业结束时PS并未立即随之增大,在24h内它随时间而发展,但到第4小时已达最高水平,且条件反应率是与PS的水平相应的,对PS与EPSPs的斜率进行相关分析表明,PS的变化主要是突触传递功效的变化。上述结果表明,海马CA_3区随着行为训练有习得性LTP产生。从其发神变化特点及其与条件性行为的关系,提示此习得性LTP极其可能是本实验中学习和记忆的展经基础。     

Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor

Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a pre-synaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were normal. Importantly, escape latency in the water maze in EP2 KO was longer than that in age-matched EP2 wild-type littermates (WT). We also observed that long-term potentiation was potentiated in EP2 WT animals that received lipopolysaccharide (LPS, i.p.), but not in EP2 KO. Bath application of PGE2 or butaprost, an EP2 receptor agonist, increased synaptic transmission and decreased paired-pulses ratio in EP2 WT mice, but failed to induce the changes in EP2 KO mice. Meanwhile, synaptic transmission was elevated by application of forskolin, an adenylyl cyclase activator, both in EP2 KO and WT animals. In addition, the PGE2-enhanced synaptic transmission was significantly attenuated by application of PKA, IP3 or MAPK inhibitors in EP2 WT animals. Our results show that hippocampal long-term synaptic plasticity is impaired in mice deficient in the EP2, suggesting that PGE2-EP2 signaling is important for hippocampal long-term synaptic plasticity and cognitive function.     

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。     

Contribution of Postsynaptic AMPA Receptor Channels to the Short- and Long-Term Synaptic Plasticity

The author briefly summarizes his own experimental data obtained earlier and reports evidence in favor of the contribution of postsynaptic AMPA receptor channels to the mechanisms underlying modifications of excitatory synaptic transmission in the CNS (in particular, in neocortical and hippocampal neuronal circuits).     

Effects of matrix metalloproteinase inhibition on short- and long-term plasticity of schaffer collateral/CA1 synapses

It is increasingly evident that matrix metalloproteinases (MMPs), a family of zinc containing extracellular endopeptidases, participate in processes supporting hippocampal synaptic plasticity. The purpose of this study was to further the understanding of MMPs involvement in hippocampal plasticity. Acute hippocampal slices, generated from 20- to 30-day-old male Sprague-Dawley rats, were subjected to various electrophysiologic stimulatory paradigms to produce either short-term or long-term modifications to synaptic efficacy. Slices exposed to broad-spectrum MMP inhibitor, FN-439, exhibited impairments in paired-pulse facilitation, theta-burst facilitation, and long-term depression. Additionally, we observed that MMP inhibition impaired both the induction and stability of long-term potentiation (LTP). Furthermore, evidence indicated that the effect of MMP inhibition on LTP maintenance is dependent upon integrin-directed adhesion, whereas the effects of MMP inhibition on LTP induction are independent of integrin-directed adhesion. Together, these data support a generalized role for MMPs in short-term and long-term hippocampal plasticity and indicate that MMPs are a necessary facet of integrin-mediated cell adhesion supporting LTP stabilization.     

Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.     

Synaptic plasticity in a regenerated crayfish phasic motoneuron

Crustacean neuromuscular systems provide many advantages for the study of synaptic transmission and plasticity. The present study examines aspects of synaptic transmission in the phasic, fast closer excitor (FCE) motoneuron of regenerated crayfish claws. Excitatory postsynaptic potentials (EPSPs) fatigued rapidly and showed poor long-term facilitation (LTF) in the smallest of regenerating claws. EPSPs in larger regenerating claws fatigued less and showed pronounced facilitation. These observations were not the same as those previously made during primary development of this motoneuron (Lnenicka and Atwood, 1985a, J. Neuroscience 5:459–467). Hence, regeneration is not the recapitulation of primary development. In situ stimulation of the FCE is known to lead to long-lasting adaptation of synaptic performance. This adaptation is age dependent; it is expressed in young but not old animals. In the regenerated FCE of old animals, we observed a novel form of long-lasting adaptation to imposed activity: EPSPs showed large initial EPSPs and did not exhibit resistance to fatigue during maintained stimulation. This indicates that aged motoneurons can express adaptive changes to increased activity following axonal regeneration, but that the adaptive changes are the opposite to what is observed in nonregenerated motoneurons. © 1992 John Wiley & Sons, Inc.     

Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.     

Participation of CaMKII in neuronal plasticity and memory formation

1. The unique biochemical properties of Ca²⁺/calmodulin (CaM)-dependent protein kinase II have made this enzyme one of the paradigmatic models of the forever searched memory molecule.2. In particular, the central participation of CaMKII as a sensor of the Ca²⁺ signals generated by activation of NMDA receptors after the induction of long-term plastic changes, has encouraged the use of pharmacological, genetic, biochemical, and imaging tools to unveil the role of this kinase in the acquisition, consolidation, and expression of different types of memories.3. Here we review some of the more exciting discoveries related to the mechanisms involved in CaMKII activation and synaptic plasticity.     

Leptin regulation of hippocampal synaptic function in health and disease

The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer''s disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.     

突触可塑性与脑疾病的神经发育基础

大脑神经回路高度有序的神经元活动是高级脑功能的基础,神经元之间的突触联结是神经回路的关键功能节点。神经突触根据神经元活动调整其传递效能的能力,亦即突触可塑性,被认为是神经回路发育和学习与记忆功能的基础。其异常则可能导致如抑郁症和阿尔茨海默病等精神、神经疾病。将介绍这两种疾病与突触可塑性的关系,聚焦于相关分子和细胞机制以及新的研究、治疗手段等进展。     

NMDA receptor activation results in PKA- and ERK-dependent Mnk1 activation and increased eIF4E phosphorylation in hippocampal area CA1

Protein synthesis is essential for the stabilization of glutamate receptor-dependent forms of long-lasting hippocampal synaptic plasticity and for the consolidation of memory, but the signal transduction mechanisms that regulate translation factors during these processes are not well understood. As a first step towards understanding how translation is activated during synaptic plasticity, we investigated how the eukaryotic initiation factor 4E (eIF4E), a rate-limiting mRNA cap-binding protein, and its kinase, Mnk1, are regulated by protein kinase C (PKC), cAMP-dependent protein kinase (PKA) and N-methyl-D-aspartate (NMDA) receptor activation in hippocampal area CA1. We found that treatment of mouse hippocampal slices with either phorbol ester, to activate PKC, or forskolin, to activate PKA, resulted in activation of Mnk1 and increased eIF4E phosphorylation that was dependent on extracellular signal-regulated kinase (ERK). Similarly, brief treatment of hippocampal slices with NMDA resulted in activation of Mnk1 and increased phosphorylation of eIF4E. The NMDA-induced activation of Mnk1 and increased phosphorylation of eIF4E were dependent on PKA and ERK, but not PKC, and were present in synaptoneurosome preparations. Immunohistochemical analysis revealed that the PKA- and ERK-dependent increases in Mnk1 activation induced by NMDA also occurred in dendrites. These findings identify a specific regulatory pathway that can couple NMDA receptor activation to translation initiation factors in the hippocampus, and may represent a mechanism for triggering dendritic protein synthesis during long-term potentiation and long-term memory formation.