Dynamics Of Excitatory Synaptic Transmission In The CNS

中枢神经系统兴奋性突触传递的动力学

• 批准号: 7324622
• 负责人: JEFFREY S DIAMOND
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7324622
• 关键词: Dynamics; Excitatory; Synaptic; Transmission; CNS

The brain transduces sensory stimuli, processes information and stores memory within large networks of neurons linked together by synaptic connections. Our laboratory is working to understand what particular features of synapses affect their strength, reliability and independence, and how these attributes contribute to their role in the function of the network. Chemical synaptic connections are made through the release of diffusible neurotransmitter molecules that bind to receptors on the recipient neuron; recent evidence suggests that the neurotransmitter may escape the synapse in which it is released and diffuse into neighboring synapses. This "spillover" of neurotransmitter between synapses could have a profound impact on the information capacity of neural networks and the rules governing their construction during development. We have worked to determine the extent to which the excitatory neurotransmitter glutamate spills over between synapses in the hippocampus, a major site of learning and memory storage in the brain, and in the retina, where visual stimuli are encoded for transmission along the optic nerve. Using electrophysiological techniques in acutely prepared slices of rat retina and hippocampus, we have found that glutamate escapes the synapse from which it is released and diffuses into neighboring synapses. This diffusion is tightly regulated by glutamate transporters, pump proteins located primarily on glial membranes that bind glutamate and remove it from the extracellular fluid (Diamond, 2005). Work is continuing to investigate the modulation of these mechanisms and their impact on information processing in hippocampal and retinal neural networks. We have become particularly interested in how neuronal glutamate transporters, which are much less numerous than those on glia but nonetheless appear to limit epileptogenesis, contribute to the clearance of neurotransmitter and the specificity of synaptic connections. In the retina, we find that certain types of receptors may be localized specifically to limit their activation under certain conditions. On ganglion cells, NMDA-type glutamate receptors are located perisynaptically (Zhang and Diamond, 2006), such that their activation is prevented by glutamate transporters unless many vesicles of glutamate are released simultaneously. More recent work in the lab indicates that these perisynaptic receptors extend the range over which ganglion cells respond to light stimulation. We currently are exploring how NMDA receptors contribute differently to synaptic signaling in the ON and OFF retinal pathways. We also have increased our study of inhibitory synaptic connections made by amacrine cells within the inner retina, to understand how feedforward and feedback inhibition contributes to signal processing in this network. We find that A17 amacrine cells provide rapid GABAergic feedback to rod bipolar cell terminals via a release process that is independent of membrane depolarization or voltage-gated calcium channels (Chavez, et al., 2006). This rapid feedback, driven by activation of calcium-permeable AMPA receptors in the A17 amacrine cell, may be essential to prevent the rapid depletion of readily-releasable vesicles from the rod bipolar cell synaptic terminal (Singer and Diamond, 2006).

大脑传递感官刺激，处理信息，并在由突触连接在一起的神经元网络中存储记忆。我们的实验室正在努力了解突触的哪些特定特征会影响它们的强度、可靠性和独立性，以及这些属性如何影响它们在网络功能中的作用。化学突触连接是通过释放可扩散的神经递质分子来实现的，这些递质分子与受体神经元上的受体结合；最近的证据表明，神经递质可能会逃离释放它的突触，扩散到邻近的突触。神经递质在突触之间的这种“溢出”可能对神经网络的信息容量和发育过程中控制其构建的规则产生深远的影响。我们已经确定了兴奋性神经递质谷氨酸在海马体突触和视网膜突触之间溢出的程度。海马体是大脑中学习和记忆存储的主要部位，视网膜是视觉刺激被编码并沿着视神经传递的地方。我们利用电生理技术在大鼠视网膜和海马的急性制备切片中发现，谷氨酸从其释放的突触中逃脱并扩散到邻近的突触中。这种扩散受到谷氨酸转运蛋白的严格调控，谷氨酸转运蛋白主要位于胶质膜上，与谷氨酸结合并将其从细胞外液中移除（Diamond, 2005）。研究人员正在继续研究这些机制的调节及其对海马和视网膜神经网络信息处理的影响。我们特别感兴趣的是，神经元谷氨酸转运蛋白的数量比神经胶质上的少得多，但似乎限制了癫痫的发生，它们如何有助于神经递质的清除和突触连接的特异性。在视网膜中，我们发现某些类型的受体可能被特定地定位，以限制它们在某些条件下的激活。在神经节细胞上，nmda型谷氨酸受体位于突触周围（Zhang和Diamond， 2006），因此它们的激活被谷氨酸转运体阻止，除非许多谷氨酸囊泡同时释放。最近的实验室研究表明，这些突触周围受体扩大了神经节细胞对光刺激的反应范围。我们目前正在探索NMDA受体如何在视网膜通路的ON和OFF突触信号传导中发挥不同的作用。我们还增加了对视网膜内无突细胞形成的抑制性突触连接的研究，以了解前馈和反馈抑制如何有助于该网络中的信号处理。我们发现A17无分泌细胞通过一个独立于膜去极化或电压门控钙通道的释放过程，向杆双极细胞终端提供快速的gaba能反馈（Chavez等，2006）。这种由A17腺分泌细胞中钙渗透性AMPA受体激活所驱动的快速反馈，可能是防止杆状双极细胞突触末端易释放囊泡迅速耗竭所必需的（Singer和Diamond， 2006）。