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: 6843258
• 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/6843258
• 关键词: NMDA receptors; amacrine cells; central nervous system; cerebrospinal fluid; developmental neurobiology; electrophysiology; glia; glutamate transporter; glutamates; hippocampus; laboratory rat; neural information processing; neural transmission; neurotransmitter receptor; pyramidal cells; receptor binding; retina; retinal ganglion; synapses; visual stimulus

The brain stores information in patterns of synaptic connections within large networks of neurons. New information is incorporated into a neural network through the modification of connections via mechanisms that are incompletely understood. One fundamental question is whether individual connections behave independently, or whether they are influenced by the activity of neighboring synapses. 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 synaptic connections would have a profound impact on the information capacity of neural networks and the mechanisms by which they are constructed during development. Work in this laboratory is directed towards determining whether 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 is 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 cerebrospinal fluid. Moreover, it appears that the electrical state of the recipient neuron influence whether the receptors are responsive to low levels of glutamate released from a distant synapse. Work is continuing to investigate the modulation of these mechanisms and their impact on information processing in networks of neurons. In addition, we are recording transporter-mediated synaptic responses in hippocampal astrocytes in an effort to estimate more quantitatively how fast synaptically released glutamate is cleared from the extracellular space. Glutamate appears to be taken up with 3 milliseconds following release, suggesting that it is able to diffuse 1-2 microns from its point of release. Other work in the hippocampus indicates that glutamate transporters on inhibitory synaptic terminals provide substrate for synthesis of the inhibitory transmitter GABA. This suggests a novel mechanism by which excitotoxic effects of increased extracellular glutamate levels may be offset by locally enhanced inhibition. This may be particularly important during epileptic siezure activity. Our work in the retina indicates that certain types of receptors may be localized specifically to limit their activation under certain conditions. On ganglion cells, NMDA-type glutamate receptors appear to be located perisynaptically, 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 may extend the range over which ganglion cells respond to light stimulation. Other experiments in which we record simultaneously from synaptically coupled retinal neurons indicate that ribbon synapses are capable of very fast transmitter release, even though their physiological release is slow. In addition, our experiments indicate that ribbon synapses coordinate the simultaneous release of multiple vesicles during evoked responses. These results may provide new insights into the function of the synaptic ribbon. Other work in the retina explores the inhbitiory, GABAergic feedback from A17 amacrine cells onto rod bipolar cells. This feedback appears to be mediated by a complex combination of GABA-A and GABA-C receptor-mediated components.

大脑以突触连接的模式将信息存储在大型神经元网络中。新的信息通过不完全理解的机制修改连接而被纳入神经网络。一个基本的问题是，各个连接是否独立地起作用，或者它们是否受到相邻突触活动的影响。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。突触连接之间的神经递质的这种“溢出”将对神经网络的信息容量以及它们在发育过程中构建的机制产生深远的影响。这个实验室的工作是确定兴奋性神经递质谷氨酸是否溢出海马体和视网膜中的突触之间，海马体是大脑中学习和记忆存储的主要场所，而视网膜中的视觉刺激是编码的，以便沿着视神经传输。利用电生理技术在急性制备的大鼠视网膜和海马切片中，我们发现谷氨酸从释放它的突触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脑脊液中清除。此外，似乎受体神经元的电状态影响受体是否对从远端突触释放的低水平谷氨酸有反应。目前正在继续研究这些机制的调制及其对神经元网络信息处理的影响。此外，我们正在记录转运蛋白介导的海马星形胶质细胞中的突触反应，以更定量地估计突触释放的谷氨酸从细胞外间隙清除的速度。谷氨酸似乎在释放后3毫秒内被吸收，表明它能够从其释放点扩散1-2微米。 海马体中的其他研究表明，抑制性突触末梢上的谷氨酸转运体为抑制性递质GABA的合成提供底物。这表明了一种新的机制，通过这种机制，细胞外谷氨酸水平增加的兴奋性毒性作用可能会被局部增强的抑制所抵消。这在癫痫发作期间可能特别重要。 我们在视网膜中的工作表明，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型谷氨酸受体似乎位于突触周围，因此它们的激活被谷氨酸转运蛋白阻止，除非同时释放许多谷氨酸囊泡。实验室最近的工作表明，这些突触周围受体可能会扩大神经节细胞对光刺激的反应范围。 我们同时记录突触耦合视网膜神经元的其他实验表明，带状突触能够非常快速地释放递质，即使它们的生理释放是缓慢的。此外，我们的实验表明，带状突触协调多个囊泡在诱发反应的同时释放。这些结果可能为了解突触带的功能提供新的见解。 视网膜中的其他工作探索了从A17无长突细胞到视杆双极细胞的抑制性GABA能反馈。这种反馈似乎是由GABA-A和GABA-C受体介导的成分的复杂组合介导的。