Dynamics Of Excitatory Synaptic Transmission In The Hippocampus

海马兴奋性突触传递的动力学

• 批准号: 7969593
• 负责人: JEFFREY S DIAMOND
• 金额: $ 34.99万
• 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/7969593
• 关键词: Adult; Affect; Affinity; Alzheimer' s Disease; Binding; Biological Neural Networks; Brain; Buffers; Chemicals; Collaborations; Development; Diffuse; Diffusion; Epileptogenesis; Extracellular Fluid; Genetic; Genetic Models; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Hippocampus (Brain); Laboratories; Learning; Link; Long-Term Potentiation; Measures; Membrane; Memory; Mus; Neonatal; Neuroglia; Neurons; Neurotransmitters; Paper; Pharmaceutical Preparations; Preparation; Process; Proteins; Pump; Receptor Activation; Relative (related person); Retinal; Role; Site; Slice; Specificity; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Time; Universities; Washington; Work; cooking; critical period; extracellular; information processing; interest; mouse model; receptor; research study; sensory stimulus; spatiotemporal; stimulus processing; synaptogenesis; tool; uptake; voltage

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. Using electrophysiological techniques in acutely prepared slices of mouse 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. 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. Our most recent work, which has been submitted, indicates for the first time that neuronal transporters in the hippocampus buffer synaptically released glutamate close to its site of release, delaying its diffusion out of the perisynaptic region and limiting its activation of extrasynaptic NMDARs. Interestingly, these transporters appear to impact synaptic plasticity by regulating the activation of a particular subtype of NMDAR, the NR2B-subunit- containing NMDAR. We find that genetic deletion of neuronal transporters leads to a decrease in long-term potentiation (LTP) that can be reversed (rescued) by a drug that specifically blocks NR2B-containing receptors. Given that these transporters are voltage-dependent, we speculate that they may underlie an activity-dependent modulation of synaptic plasticity. The rules governing receptor activation and activity-dependent plasticity in the neonatal hippocampus is poorly understood, but this is a critical period of synapse formation and network assembly. Interestingly, glutamate uptake is much less capacious in neonatal hippocampus, suggesting that glutamate may diffuse further to activate receptors at a greater distance and implicating a different set of rules for synaptic plasticity. Our results suggest that the lower transporter expression is offset by a much greater extracellular volume, such that synaptic specificity of nascent synapses may be maintained more by dilution of transmitter rather than uptake. A paper describing this work is in preparation. We also have begin a collaboration with David Cook at the University of Washington to measure quantitatively the time course of glutamate uptake in a mouse model of Alzheimer's Disease.

大脑在由突触连接连接在一起的大型神经元网络中转换感官刺激，处理信息并存储记忆。 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，以及这些属性如何有助于它们在网络功能中的作用。 化学突触连接是通过释放与受体神经元上的受体结合的可扩散神经递质分子来实现的;最近的证据表明，神经递质可能会逃离释放它的突触并扩散到相邻的突触中。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影响。我们致力于确定兴奋性神经递质谷氨酸在海马体突触之间溢出的程度，海马体是大脑中学习和记忆储存的主要场所。 利用电生理学技术，在急性制备的小鼠海马切片中，我们发现谷氨酸从释放它的突触中逃逸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节，谷氨酸转运蛋白主要位于神经胶质细胞膜上，结合谷氨酸并将其从细胞外液中清除。 目前正在继续研究这些机制的调制及其对海马和视网膜神经网络信息处理的影响。 我们已经成为特别感兴趣的是，神经元谷氨酸转运体，这是数量少得多，比神经胶质细胞，但似乎限制癫痫发生，有助于清除神经递质和突触连接的特异性。 我们最近的工作，这已经提交，首次表明，在海马缓冲神经元转运突触释放谷氨酸接近其网站的释放，延迟其扩散出突触周围区域，并限制其激活的突触外NMDAR。 有趣的是，这些转运蛋白似乎通过调节NMDAR的特定亚型（含NR 2B亚基的NMDAR）的激活来影响突触可塑性。 我们发现，神经元转运蛋白的基因缺失导致长时程增强（LTP）的减少，这可以通过特异性阻断含NR 2B受体的药物逆转（拯救）。 鉴于这些转运蛋白是电压依赖性的，我们推测它们可能是突触可塑性的活性依赖性调制的基础。 新生儿海马中受体激活和活动依赖性可塑性的规则知之甚少，但这是突触形成和网络组装的关键时期。 有趣的是，谷氨酸摄取在新生儿海马中的容量要小得多，这表明谷氨酸可能进一步扩散以激活更远距离的受体，并暗示了一套不同的突触可塑性规则。 我们的研究结果表明，较低的转运蛋白的表达是抵消了一个更大的细胞外体积，这样的新生突触的突触特异性可以保持更多的稀释的发射，而不是摄取。 正在编写一份介绍这项工作的文件。 我们还开始与华盛顿大学的大卫库克合作，定量测量阿尔茨海默病小鼠模型中谷氨酸摄取的时间过程。