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。     

NMDA受体的结构及其生理作用

N-甲基-D-天冬氨酸（NMDA）受体是离子型兴奋性谷氨酸受体的一种亚型,生物体内已发现了3种NMDA受体亚基,且通过选择性剪接至少存在7种亚型,形成具有功能的多结合位点的大分子复合物。NMDA受体在中枢神经系统的突触传递、突触可塑性、学习记忆等生理过程中发挥着重要作用,且NMDA受体的异常会导致-些精神疾病及认知功能的障碍。     

N-甲基-D-天氡氨酸受体的分子结构与生理功能

NMDA（N-甲基-D-天氡氨酸）受体是离子型谷氨酸受体的一种亚型,在中枢神经系统的突触传递和突触可塑性调节中起着重要的作用。生物体内已经发现了三种NMDA受体亚基,通过基因的选择性剪切可产生多种亚单位。NMDA受体是一个具有多个结合位点的大分子复合物,其生理特性同异聚体通道的装配密切相关。NMDA受体的异常会导致一些认知功能的缺失,这为治疗性药物开发提供了靶点。     

N-甲基-D-天氡氨酸受体的分子结构与生理功能

N-甲基-D-天氡氨酸（NMDA）受体是离子型谷氨酸受体的一种亚型,在中枢神经系统的突触传递和突触可塑性调节中起着重要的作用。延长NMDA受体活动时间将导致兴奋毒性。NMDA受体是一个具有多个结合位点的大分子复合物,其生理特性同异聚体通道的装配密切相关。NMDA受体的异常会导致一些认知功能的缺失,这为治疗性药物开发提供了靶点。     

突触上与突触外的NMDA受体及其与阿尔茨海默病关系的研究进展

突触上的N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体与学习记忆以及细胞的存活有着密切关系,而定位于突触外的NMDA受体则参与了细胞死亡通路的激活.本文主要从突触NMDA受体的结构和功能出发,阐述突触上与突触外NMDA受体分布的原因,阐明其介导不同信号通路的具体分子机制及其在阿尔茨海默病(Alzheimer's disease,AD)中扮演的角色.最后,以突触外的NMDA受体为靶点,对AD疾病的治疗提出合理的展望,以期推动对该疾病的研究和治疗.     

一种兴奋性氨基酸受体亚型

N-甲基-D-门冬氨酸(NMDA)受体是一种兴奋性氨基酸受体,广泛分布于许多脑区。该受体被激活后,突触后膜产生一长时程的兴奋性突触后电位,进而引起多种神经生物学效应或神经毒性作用。Ca~(2 )对于NMDA受体效应的产生具有重要意义。     

谷氨酸性突触在痛觉和记忆中的突触和分子机制

谷氨酸是哺乳动物脑中的兴奋性递质。中枢神经系统的谷氨酸性突触广泛参与痛觉传递,突触可塑性和递质的调节。谷氨酸的NMDA受体参与前脑相关的学习及功能。在这篇综述中,我们提出前脑的NMDA受体通过增强谷氨酸性突触传递导致长期性的炎痛。具有增强NMDA受体功能的小鼠会产生更多的慢性痛。NMDA NR2B受体抑制剂在未来可能被用来控制人类的慢性痛。     

成年小鼠前脑NMDA受体参与神经元的动作电位发放

谷氨酸是中枢神经系统主要的快速兴奋性递质。AMPA受体和海人藻酸受体主要参与突触传递,而NMDA受体主要参与突触可塑性。基因操作的方法增强NMDA受体的功能,可以增强动物在正常生理状态下的学习能力,及在组织损伤情况下的反应敏感性。NMDA受体参与生理功能的主要机制是长时程增强（long—term potentiation,LTP）。我们的研究表明,NMDA受体不仅参与刺激前扣带皮层的第五层细胞或刺激白质诱导的突触反应,而且参与在胞体施加去极化跃阶电流诱导的动作电位的发放。钙一钙调蛋白敏感的腺苷酸环化酶1（adenylyl cyclase 1,AC1）和cAMP信号通路可能介导了这些反应。由于扣带皮层神经元在伤害性刺激和痛中发挥重要作用,我们的结果为前脑NMDA受体参与突触传递和动作电位发放,以及与前脑相关的行为,如感受伤害性刺激和痛,提供了一个新的机制。     

PSD—95对NMDA受体信号转导的整合作用

PSD－95是新近在谷氨酸能突触的突触后致密物（PSD）中发现的一种特殊蛋白质,含有3个N末端的PDZ结构域,一个SH3结构域和一个C末端的GK结构域。PSD－95通过不同结构域与其它蛋白相互作用,不仅能够串集NMDA受体及其信号通路中的相关蛋白分子,组成受体－信号分子－调节分子－靶分子复合物,还可通过突触前后粘附分子的相互作用,参与突触连接的形成和维持,在介导和整合NMDA受体信号转导中具有关键性作用。     

N-甲基-D-门冬氨酸受体通道复合体

N-甲基-D门冬氨酸(NMDA)受体通道复合体不同于一般的递质门控或电压门控的离子通道,而是兼有递质门控与电压门控双重特征。该受体通道有四种以上不同的电导水平,因而可能是多个受体亚型结合的一个复合的分子实体。NMDA受体通道的开放可引起钠、钾、钙离子内流。已经发现NMDA受体通道与长时程突触增强,癫痫等脑活动有关。     

NR2A and NR2B subunits differentially mediate MAP kinase signaling and mitochondrial morphology following excitotoxic insult

NMDA receptors are essential for neurotransmission and key mediators of synaptic signaling, but they can also trigger deleterious degenerative processes that lead to cell death. Growing evidence suggests that selective blockade of the heterogeneous subunits that comprise the NMDA receptor may enable better control of pharmacotherapies for treating neurological diseases and injuries. We investigated the relationship between NMDAR activation, MAPK signaling, and mitochondrial shape following an excitotoxic insult. NR2A- and NR2B-containing NMDARs differentially mediated acute changes in cytosolic calcium, alterations in mitochondrial morphology, and phosphorylation of the MAPKs ERK and JNK. Activation of NR2A-containing NMDARs was associated with JNK phosphorylation that was neuroprotective in neuronal cultures subjected to excitotoxicity. In contrast, activation of NR2B-containing NMDARs triggered calcium accumulation in mitochondria that was strongly associated with mitochondrial swelling and neuronal cell death. Indeed, while blockade of NR2B-containing receptors was neuroprotective, this protection was lost when NR2A-initiated JNK phosphorylation was inhibited. Given the modest selectivity of the NR2A inhibitor, NVP-AAM077, the results highlight the significance of the relative, rather than absolute, activation of these two NMDA subtypes in modulating cell death pathways. Therefore, the balance between concurrent activation of NR2B-containing and NR2A-containing NMDARs dictates neuronal fate following excitotoxicity.     

The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation

N-Methyl-D-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.     

AMPA receptor-dependent clustering of synaptic NMDA receptors is mediated by Stargazin and NR2A/B in spinal neurons and hippocampal interneurons

Under standard conditions, cultured ventral spinal neurons cluster AMPA- but not NMDA-type glutamate receptors at excitatory synapses on their dendritic shafts in spite of abundant expression of the ubiquitous NMDA receptor subunit NR1. We demonstrate here that the NMDA receptor subunits NR2A and NR2B are not routinely expressed in cultured spinal neurons and that transfection with NR2A or NR2B reconstitutes the synaptic targeting of NMDA receptors and confers on exogenous application of the immediate early gene product Narp the ability to cluster both AMPA and NMDA receptors. The use of dominant-negative mutants of GluR2 further showed that the synaptic targeting of NMDA receptors is dependent on the presence of synaptic AMPA receptors and that synaptic AMPA and NMDA receptors are linked by Stargazin and a MAGUK protein. This system of AMPA receptor-dependent synaptic NMDA receptor localization was preserved in hippocampal interneurons but reversed in hippocampal pyramidal neurons.     

Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking

NMDA receptors (NMDARs) control bidirectional synaptic plasticity by regulating postsynaptic AMPA receptors (AMPARs). Here we show that NMDAR activation can have differential effects on AMPAR trafficking, depending on the subunit composition of NMDARs. In mature cultured neurons, NR2A-NMDARs promote, whereas NR2B-NMDARs inhibit, the surface expression of GluR1, primarily by regulating its surface insertion. In mature neurons, NR2B is coupled to inhibition rather than activation of the Ras-ERK pathway, which drives surface delivery of GluR1. Moreover, the synaptic Ras GTPase activating protein (GAP) SynGAP is selectively associated with NR2B-NMDARs in brain and is required for inhibition of NMDAR-dependent ERK activation. Preferential coupling of NR2B to SynGAP could explain the subtype-specific function of NR2B-NMDARs in inhibition of Ras-ERK, removal of synaptic AMPARs, and weakening of synaptic transmission.     

Polymodal Regulation of NMDA Receptor-Channels

Glutamate-activated N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels which mediate synaptic transmission, long-term potentiation, synaptic plasticity and neurodegeneration via conditional Ca2+ signalling. Recent crystallographic studies have focussed on solving the structural determinant of the ligand binding within the core region of NR1 and NR2 subunits. Future structural analysis will help to understand the mechanism of native channel activation and regulation during synaptic transmission. A number of NMDA receptor ligands have been identified which act as positive or negative modulators of receptor function. There is evidence that the lipid bilayer can further regulate the activity of the NMDA receptor channels. Modulators of NMDA receptor function offer the potential for the development of novel therapeutics to target neurological disorders associated with this family of glutamate ion channel receptors. Here, we review the recent literature concerning structural and functional properties, as well as the physiological and pathological roles of NMDA receptor channels.     

Polymodal regulation of NMDA receptor channels

Glutamate-activated N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels, which mediate synaptic transmission, long-term potentiation, synaptic plasticity and neurodegeneration via conditional Ca(2+) signalling. Recent crystallographic studies have focussed on solving the structural determinant of the ligand binding within the core region of NR1 and NR2 subunits. Future structural analysis will help to understand the mechanism of native channel activation and regulation during synaptic transmission. A number of NMDA receptor ligands have been identified which act as positive or negative modulators of receptor function. There is evidence that the lipid bilayer can further regulate the activity of the NMDA receptor channels. Modulators of NMDA receptor function offer the potential for the development of novel therapeutics to target neurological disorders associated with this family of glutamate ion channel receptors. Here, we review the recent literature concerning structural and functional properties, as well as the physiological and pathological roles of NMDA receptor channels.     

Synaptic activity-dependent developmental regulation of NMDA receptor subunit expression in cultured neocortical neurons

The biophysical properties of NMDA receptors are thought to be critical determinants involved in the regulation of long-term synaptic plasticity during neocortical development. NMDA receptor channel properties are strongly dependent on the subunit composition of heteromeric NMDA receptors. During neocortical development in vivo, the expression of the NMDA receptor 2A (NR2A) subunit is up-regulated at the mRNA and protein level correlating with changes in the kinetic and pharmacological properties of functional NMDA receptors. To investigate the developmental regulation of NMDA receptor subunit expression, we studied NR2 mRNA expression in cultured neocortical neurons. With increasing time in culture, they showed a similar up-regulation of NR2A mRNA expression as described in vivo. As demonstrated by chronic blockade of postsynaptic glutamate receptors in vitro, the regulation of NR2A mRNA was strongly dependent on synaptic activity. In contrast, NR2B mRNA expression was not influenced by activity blockade. Moreover, as shown pharmacologically, the regulation of NR2A mRNA expression was mediated by postsynaptic Ca(2+) influx through both NMDA receptors and L-type Ca(2+) channels. It is interesting that even relatively weak expression of NR2A mRNA was correlated with clearly reduced sensitivity of NMDA receptor-mediated whole-cell currents against the NR2B subunit-specific antagonist ifenprodil. Developmental changes in the expression of NR1 mRNA splice variants were also strongly dependent on synaptic activity and thus might, in addition to regulation of NR2 subunit expression, contribute to developmental changes in the properties of functional NMDA receptors. In summary, our results demonstrate that synaptic activity is a key factor in the regulation of NMDA receptor subunit expression during neocortical development.     

NR2A-containing NMDA receptors depress glutamatergic synaptic transmission and evoked-dopamine release in the mouse striatum

NMDA receptors play essential roles in the physiology and pathophysiology of the striatum, a brain nucleus involved in motor control and reward-motivated behaviors. NMDA receptors are composed of NR1 and NR2A–D subunits. Functional properties of NMDA receptors are determined by the type of NR2 subunit they contain. In this study, we have examined the involvement of NR2B and NR2A in the modulatory effect of NMDA on glutamatergic and dopaminergic synaptic transmission in the striatum. We found that bath application of NMDA decreased the amplitude of the field excitatory post-synaptic potential/population spike (fEPSP/PS) measured in corticostriatal mouse brain slices. This depression was not affected by the NR2B-selective antagonists Ifenprodil and Ro 25-6981, but was abolished by the NR2A antagonist NVP-AAM077. Activation of corticostriatal neurons by NMDA did not contribute to synaptic depression because similar results were obtained in decorticated striatal slices. Synaptic depression was not dependent on GABA release because the GABA_A receptor antagonist bicuculline did not affect NMDA-induced decrease of the fEPSP/PS. NMDA also depressed evoked-dopamine release through NR2A- but not NR2B-containing NMDA receptors. Our results identify an important role for NR2A-containing NMDA receptors intrinsic to the striatum in regulating glutamatergic synaptic transmission and evoked-dopamine release.     

Spatial memory formation induces recruitment of NMDA receptor and PSD-95 to synaptic lipid rafts

NMDA receptors (NMDARs) activation in the hippocampus and insular cortex is necessary for spatial memory formation. Recent studies suggest that localization of NMDARs to lipid rafts enhance their signalization, since the kinases that phosphorylate its subunits are present in larger proportion in lipid raft membrane microdomains. We sought to determine the possibility that NMDAR translocation to synaptic lipid rafts occurs during plasticity processes such as memory formation. Our results show that water maze training induces a rapid recruitment of NMDAR subunits (NR1, NR2A, NR2B) and PSD-95 to synaptic lipid rafts and decrease in the post-synaptic density plus an increase of NR2B phosphorylation at tyrosine 1472 in the rat insular cortex. In the hippocampus, spatial training induces selective translocation of NR1 and NR2A subunits to lipid rafts. These results suggest that NMDARs translocate from the soluble fraction of post-synaptic membrane (non-raft PSD) to synaptic lipid raft during spatial memory formation. The recruitment of NMDA receptors and other proteins to lipid rafts could be an important mechanism for increasing the efficiency of synaptic transmission during synaptic plasticity process.     

Subcellular segregation of distinct heteromeric NMDA glutamate receptors in the striatum

Functional N-methyl-d-aspartate (NMDA) glutamate receptors are composed of heteromeric complexes of NR1, the obligatory subunit for channel activity, and NR2 or NR3 family members, which confer variability in the properties of the receptors. Recent studies have provided evidence for the existence of both binary (containing NR1 and either NR2A or NR2B) and ternary (containing NR1, NR2A, and NR2B) receptor complexes in the adult mammalian brain. However, the mechanisms regulating subunit assembly and receptor localization are not well understood. In the CNS, NMDA subunits are present both at intracellular sites and the post-synaptic membrane of neurons. Using biochemical protein fractionation and co-immunoprecipitation approaches we have found that in rat striatum binary NMDA receptors are widely distributed, and can be identified in the light membrane, synaptosomal membrane, and synaptic vesicle-enriched subcellular compartments. In contrast, ternary receptors are found exclusively in the synaptosomal membranes. When striatal proteins are chemically cross-linked prior to subcellular fractionation, ternary NMDA receptors can be precipitated from the light membrane and synaptic vesicle-enriched fractions where this type of receptor complex is not detectable under normal conditions. These findings suggest differential targeting of distinct types of NMDA receptor assemblies between intracellular and post-synaptic sites based on subunit composition. This targeting may underlie important differences in the regulation of the transport pathways involved in both normal as well as pathological receptor functions.