癫痫突触可塑性的研究动态

癫痫的形成与大脑神经元之间异常突触联系和病理性神经环路的建立而导致的兴奋性增强有关,这些异常突触联系和病理性神经环路也是突触可塑性的表现。通过癫痫点燃动物模型、癫痫状态和癫痫形成机制的研究表明,长时程增强（LTP）、NF-kB基因调控蛋白、苔藓纤维出芽（MFS）、神经肽Y（NPY）、NCAM以及谷氨酸受体NMDA型和KA型等,均参与神经元突触可塑性的过程,在癫痫的发生机制中起着重要作用。     

Gephyrin：抑制性突触后蛋白网络的核心骨架蛋白

Gephyrin是中枢神经系统(CNS)抑制性突触后蛋白网络的核心骨架蛋白,具有参与抑制性突触形成、稳定抑制性突触受体、调节突触可塑性等作用。Gephyrin翻译后修饰对Gephyrin功能的正常发挥具有重要调节作用。Gephyrin结构和功能异常与癫痫、精神分裂症等多种神经精神疾病的发生有关。     

胶质细胞源性神经营养因子与癫痫研究进展

癫痫形成和发展与神经损害密切相关。癫痫发作的启动因子是神经损伤,而癫痫发作又进一步加重神经损伤,导致恶性循环。胶质细胞源性神经营养因子（g1ialCeHline-derived neurotrophie factor,GDNF）具有促进受损神经元存活、调节突触可塑性、刺激轴突生长等多方面的生理功能。虽然癫痫损伤本身可启动中枢神经系统的神经保护机制而促进内源性GD-NF的释放,但是GDNF的释放可能存在持续时间短及分泌量不足的情况,因此,提高内源性GDNF的表达和分泌,都将成为治疗各种癫痫的一个方向。     

癫痫与抑郁障碍共患关联机制的研究进展

抑郁症是癫痫最常见的共患精神障碍,提示癫痫与抑郁障碍可能存在很多共同的发病机制,如神经递质、神经肽及其受体、神经胶质细胞、免疫介质、神经信号转导通路、突触可塑性与神经再生等。     

海马苔藓纤维出芽与癫痫

海马苔藓纤维出芽（mossy fiber sprouting,MFS）是指齿状回颗粒细胞轴突异常出芽,与内分子层颗粒细胞形成突触。它由海马神经元丢失及癫痫发作的兴奋毒性导致,牵涉导向分子、神经营养因子及神经递质等多种分子,可增高癫痫发作的敏感性,被认为与癫痫反复自发性发作（spontaneous recurrent seizures,SRS）密切相关。     

卒中后认知功能康复与神经可塑性

中枢神经系统(central nervous system，CNS)神经细胞之间有广泛神经纤维联系，各个脑功能区之间有丰富的神经纤维联络．左右大脑半球间可以通过胼胝体进行信息交流，皮质和皮质下神经结构，以及脑干、小脑间有复杂的环路，这些构成了中枢神经系统(脑)可塑性的物质形态学基础。CNS可塑性与神经细胞再生、突触可塑、神经网络重塑、脑功能重组和功能区转移等密切相关。     

沉默突触及其在神经系统疾病中的研究进展

突触可塑性是大脑可塑性的重要组成,也是脑卒中后功能恢复机制研究的重要方向,而沉默突触作为没有传递功能的突触,存在于大脑的各个时期和各个部位,其与功能性突触的转化是突触可塑性的重要表现,对进一步研究脑卒中后功能恢复的机制以及其他各种神经系统疾病的发生、发展机制具有重要意义。本文献综述表明,沉默突触存在于大脑的任何阶段（发育期、成年期或老年期）,且发挥着不同的作用,而沉默突触的形成、激活和消除机制对于研究和干预神经系统疾病具有重要意义。     

Tiam1协调突触结构和功能可塑性是神经病理性疼痛的发病基础

神经病理性疼痛是一种常见的、致残的慢性疼痛,是由躯体感觉神经系统的损伤或疾病引起的。了解神经病理性疼痛的发病机制对于开发慢性疼痛新的有效治疗策略至关重要。Tiam1是一种Rac1鸟嘌呤核苷酸交换因子,在海马发育过程中通过诱导细胞骨架重构促进树突和突触的生长。该研究使用多种神经病理性疼痛动物模型,发现Tiam1通过促进细胞骨架重构和突触NMDAR稳定性来协调脊髓背角的突触结构和功能可塑性,这些作用对于神经病理性疼痛的开始、过渡和维持至关重要。此外,针对脊髓Tiam1的反义寡核苷酸能持续缓解对神经病理性疼痛的敏感性。该研究表明Tiam1协调突触功能和结构可塑性是神经病理性疼痛病理生理学的基础。干预Tiam1介导的突触可塑性异常在神经病理性疼痛治疗中有长期影响。     

神经生长因子:抗癫痫发作新靶标

既往观念认为神经生长因子类物质具有促神经生长和修复作用,在脑外伤和脑卒中等疾病中具有神经保护作用。但近年的研究表明神经生长因子类物质参与调控神经祖细胞的增殖、分化与存活;对神经递质有选择性调控作用,在异常神经发生过程中起着至关重要的作用。神经生长因子调控轴突、树突生长,诱导神经纤维定向生长,参与癫痫疾病异常神经环路形成从而影响神经细胞兴奋性,具有诱导癫痫反复发作,促癫痫形成的作用。神经生长因子类物质可能是调控癫痫形成和进展的新靶标。     

大鼠神经干细胞与“癫痫样细胞”体外共培养后的分化发育

背景：在癫痫微环境神经干细胞能否被诱导分化为异常放电的“癫痫神经元”？癫痫微环境包括两种情况：一是“无镁”细胞外液，二是与癫痫细胞共培养。其中前者比后者的致癫痫作用强。 目的：模型模拟体内癫痫微环境，将大鼠海马神经干细胞和正常海马神经元以及“癫痫神经元”体外共培养，观察干细胞的分化发育情况。 设计：重复测量观察。 单位：哈尔滨医科大学附属第一医院。 材料：实验于2005—08／2007—04在哈尔滨医科大学病原学教研室及药理学教研室完成，选用150只新生Wistar大鼠，雌雄不拘，由哈尔滨医科大学附属第二医院实验动物中心提供，实验过程中对动物的处置符合动物伦理学标准。兔抗鼠突触素抗体购自美国LabVision公司。携带增强型绿色荧光蛋白标记基因的血清型2型腺相关病毒购自北京本元正阳公司。Axopatch 200B放大器为美国Axon公司产品。5111A示波器为美国Tektronix公司产品。 方法：①分离大鼠海马神经元，采用“无镁”外液处理神经元建立“癫痫神经元”模型。常规方法培养大鼠海马神经干细胞，将绿色荧光蛋白标记的神经干细胞分别与正常海马神经元、“癫痫神经元”共培养14d。②应用膜片钳记录与两种神经元共培养后细胞突触后电位；利用免疫荧光检测神经千细胞突触素抗体染色情况；将神经干细胞分化的神经元放入“无镁”外液，应用膜片钳记录其突触后电位。 主要观察指标：①海马神经干细胞与两种神经元共培养14d后突触后电位、突触素抗体染色结果。②分化后神经元在“无镁”外液中突触后电位及“癫痫样放电”情况。 结果：①神经干细胞与正常海马神经元共培养后，膜片钳记录到60％（6／10）神经干细胞14次，5min兴奋性突触后电位；与“癫痫神经元”共培养后记录到12次，5min兴奋性突触后电位。②神经干细胞分别与正常海马神经元及“癫痫神经元”共培养后，免疫荧光检测均显示80％（12／15）表达绿色荧光蛋白的干细胞突触素抗体染色阳性。③60％（9／15）干细胞分化的神经元在“无镁”外液中出现14次，5min时程约10s的兴奋性突触后电位，未记录到“癫痫样放电”。 结论大鼠海马神经干细胞与“癫痫神经元”体外共培养后可形成功能性突触，未转变成“癫痫神经元”。     

Multiple roles of protein kinases in the modulation of gamma-aminobutyric acid(A) receptor function and cell surface expression

gamma-Aminobutyric acid(A) (GABA(A)) receptors are ligand-gated ion channels that mediate the majority of fast synaptic inhibition in the brain and that are also important drug targets for benzodiazepines, barbiturates, and neurosteriods. These receptors are pentameric hetero-oligomers that can be assembled from 7 subunit classes with multiple members: alpha(1-6), beta(1-3), gamma(1-3), delta, epsilon, theta, and pi. Most receptor subtypes in the brain, however, are believed to be composed of alpha-, beta-, and gamma-subunits. Modifications of GABA(A) receptor function are continually implicated in a range of pathologies, including epilepsy, anxiety, insomnia, and substance abuse. Moreover, changes in the efficacy of synaptic inhibition mediated by GABA(A) receptors are believed to be play central roles in certain forms of synaptic plasticity, including rebound potentiation in the cerebellum, and hippocampal long-term potentiation. Given the critical role that GABA(A) receptors play as mediators of synaptic transmission, it is of fundamental importance to understand the endogenous mechanisms used by neurones to control the function of these receptors. This review will focus on the dynamic regulation of GABA(A) receptor phosphorylation state and channel function as mechanisms involved in determining the efficacy of synaptic inhibition. In addition, the possible role of GABA(A) receptor phosphorylation in controlling receptor internalization and recycling will also be explored.     

NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model

Background

Although the mechanism of chronic migraine (CM) is unclear, it might be related to central sensitization and neuronal persistent hyperexcitability. The tyrosine phosphorylation of NR2B (NR2B-pTyr) reportedly contributes to the development of central sensitization and persistent pain in the spinal cord. Central sensitization is thought to be associated with an increase in synaptic efficiency, but the mechanism through which NR2B-pTyr regulates synaptic participation in CM-related central sensitization is unknown. In this study, we aim to investigate the role of NR2B-pTyr in regulating synaptic plasticity in CM-related central sensitization.

Methods

Male Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections to model recurrent trigeminovascular or dural nociceptor activation, which is assumed to occur in patients with CM. We used the von Frey test to detect changes in mechanical withdrawal thresholds, and western blotting and immunofluorescence staining assays were performed to detect the expression of NR2B-pTyr in the trigeminal nucleus caudalis (TNC). NR2B-pTyr was blocked with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)-pyrazolo [3,4-d] pyrimidine (PP2) and the protein tyrosine kinase inhibitor genistein to detected the changes in calcitonin gene-related peptide (CGRP), substance P (SP), and the synaptic proteins postsynaptic density 95 (PSD95), synaptophysin (Syp), synaptotagmin1 (Syt-1). The synaptic ultrastructures were observed by transmission electron microscopy (TEM), and the dendritic architecture of TNC neurons was observed by Golgi-Cox staining.

Results

Statistical analyses revealed that repeated infusions of IS induced mechanical allodynia and significantly increased the expression of NR2B Tyr-1472 phosphorylation (pNR2B-Y1472) and NR2B Tyr-1252 phosphorylation (pNR2B-Y1252) in the TNC. Furthermore, the inhibition of NR2B-pTyr by PP2 and genistein relieved allodynia and reduced the expression of CGRP, SP, PSD95, Syp and Syt-1 and synaptic transmission.

Conclusions

These data indicate that NR2B-pTyr might regulate synaptic plasticity in central sensitization in a CM rat model. The inhibition of NR2B tyrosine phosphorylation has a protective effect on threshold dysfunction and migraine attacks through the regulation of synaptic plasticity in central sensitization.

     

Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons

It is classically recognized that regional cerebral glucose consumption (CMRglc), as measured by positron emission tomography (PET) and [18F]-2-fluorodeoxyglucose (FDG), is a precise index of the integrated local neuronal activity. However, despite extensive use of the FDG-PET method, the significance of the measured CMRglc has been little addressed so far. In the present study, we aimed for the first time to test whether resting-state CMRglc is directly related to synaptic density. To this end, we investigated in the baboon the relationships between CMR(glc) and the levels of synaptophysin (SY), a presynaptic protein classically used to assess synaptic density. CMR(glc), measured in vivo by FDG-PET at the resting-state, and SY levels, assessed postmortem by the Western blot technique, were quantified in seven brain areas of five baboons. By applying these two techniques to the same animals, we found significant positive correlations between CMR(glc) and SY levels, across all regions and all animals, as well as within individual baboons. These findings strongly support the hypothesis that resting-state CMR(glc) reflects integrated synaptic activity.     

Suppression of L-type voltage-gated calcium channel-dependent synaptic plasticity by ethanol: analysis of miniature synaptic currents and dendritic calcium transients

Intoxicating concentrations of ethanol inhibit N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation, an interaction thought to underlie a major component of the central nervous system actions of ethanol. Another form of synaptic potentiation involving activation of L-type dihydropyridine-sensitive voltage-gated calcium channels (VGCCs) has been described, but very little information concerning ethanol effects on VGCC-dependent synaptic potentiation is available. Here, we assessed ethanol effects on VGCC-dependent synaptic potentiation using whole cell patch-clamp recordings of alpha-amino-3-hydroxy-5-methyl-4-soxazolepropionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in area CA1 of the rat hippocampus. No potentiation was observed in artificial cerebrospinal fluid containing 2 to 3 mM Ca2+, but marked potentiation of mEPSCs was consistently observed in 4 mM Ca2+ and with patch pipettes containing an ATP-regenerating system. This potentiation was insensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid, whereas it was completely blocked the L-type VGCC antagonist nifedipine. Potentiation was also blocked dose dependently by bath application of ethanol (25-75 mM), which had no effect on baseline mEPSC amplitude or frequency. The synaptic potentiation involved enhancement of both presynaptic and postsynaptic components because significant increases in both the frequency and amplitude of AMPA mEPSCs were observed. Ethanol inhibition of VGCC-dependent synaptic potentiation seemed to occur at the induction step because both the increases in mEPSC frequency and amplitude were affected. To address that question more directly, we used fluorescent imaging of synaptically evoked dendritic calcium events, which displayed a similarly marked ethanol sensitivity. Thus, ethanol modulates fast excitatory synaptic transmission by inhibiting the induction of an NMDA receptor-independent form of synaptic potentiation observed at excitatory synapses on central neurons.     

运动、阿尔茨海默病与突触可塑性

运动能够减缓阿尔茨海默病(AD)的发病和进展,突触可塑性可能是AD学习和记忆功能障碍的神经生物学基础,也是运动防治AD的细胞机制。本文就运动对AD的防治作用、AD突触可塑性的改变及运动对突触可塑性的影响进行综述。     

Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats.

Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function.     

Synaptic Vesicle Docking: Sphingosine Regulates Syntaxin1 Interaction with Munc18

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients.     

Repeated oxytocin prevents central sensitization by regulating synaptic plasticity via oxytocin receptor in a chronic migraine mouse model

BackgroundCentral sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. Oxytocin (OT), which is a hypothalamic hormone, plays an important antinociceptive role. However, the antinociceptive effect of OT and the underlying mechanism in CM remains unclear. Therefore, we explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity.MethodsA CM mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and radiant heat were used to measure the nociceptive threshold. Repeated intranasal OT and intraperitoneal L368,899, an oxytocin receptor (OTR) antagonist, were administered to investigate the effect of OT and the role of OTR. The expression of calcitonin gene-related peptide (CGRP) and c-fos were measured to assess central sensitization. N-methyl D-aspartate receptor subtype 2B (NR2B)-regulated synaptic-associated proteins and synaptic plasticity were explored by western blot (WB), transmission electron microscope (TEM), and Golgi-Cox staining.ResultsOur results showed that the OTR expression in the trigeminal nucleus caudalis (TNC) of CM mouse was significantly increased, and OTR was colocalized with the postsynaptic density protein 95 (PSD-95) in neurons. Repeated intranasal OT alleviated the NTG-induced hyperalgesia and prevented central sensitization in CM mouse. Additionally, the OT treatment inhibited the overexpression of phosphorylated NR2B and synaptic-associated proteins including PSD-95, synaptophysin-1 (syt-1), and synaptosomal-associated protein 25 (snap25) in the TNC of CM mouse and restored the abnormal synaptic structure. The protective effect of OT was prevented by L368,899. Furthermore, the expression of adenylyl cyclase 1 (AC1)/ protein kinase A (PKA)/ phosphorylation of cyclic adenosine monophosphate response element-binding protein (pCREB) pathway was depressed by OT and restored by L368,899.ConclusionsOur findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via OTR in CM. The effect of OT has closely associated with the down-regulation of AC1/PKA/pCREB signaling pathway, which is activated in CM model. Repeated intranasal OT may be a potential candidate for CM prevention.     

Violet-light stimulated synaptic and learning functions in a zinc–tin oxide photoelectric transistor for neuromorphic computation

In contrast to the commonly present UV light-stimulated synaptic oxide thin-film transistors, this study demonstrates a violet light (wavelength of 405 nm) stimulated zinc–tin oxide (ZTO) photoelectric transistor for potential application in optical neuromorphic computation. Owing to the light-induced oxygen vacancy ionization and persistent photoconductivity effect in ZTO, this device well imitates prominent synaptic functions, including photonic potentiation, electric depression, and short-term memory (STM) to long-term memory (LTM) transition. A highly linear and broad dynamic range of photonic potentiation can be achieved by modulating the light power density, while electric depression is realized by gate voltage pulsing. In addition, the brain-like re-learning experience with extended forgetting time (200 s) is well mimicked by the ZTO photoelectric transistor. As a result, the ZTO photoelectric transistor provides excessive synaptic function with multi-series of synaptic weight levels (90 levels for each given light power density), which makes it prevalent in the neuromorphic computation of massive data as well as in learning-driven artificial intelligence computation.

Photonic potentiation and electric depression are realized in a ZTO thin film transistor for the application in neuromorphic computation.     

腺苷的抗抑郁作用及其相关研究

腺苷作为中枢神经系统(CNS)的重要信号分子,它以磷酸化形式(腺苷三磷酸,ATP)与神经递质一起包装在突触囊泡中被释放。弥散于突触间隙的腺苷与其A1、A2、A3三类受体结合,启动G蛋白介导的信号通路,产生广泛、灵活而多变的生物效应。近年发现,腺苷具有一定的抗抑郁疗效,但机理尚未阐明。本文就腺苷及其受体在抗抑郁作用等方面的研究进行综述。