Dynamics Of Excitatory Synaptic Transmission In The CNS

大脑在大型神经元网络中以突触连接的模式存储信息。通过不完全理解的机制，通过修改连接，将新信息合并到神经网络中。一个基本的问题是，单个连接是否独立运行，或者它们是否受到邻近突触活动的影响。突触连接是通过释放可扩散的神经递质分子来建立的，这些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，扩散到邻近的突触中。神经递质在突触连接之间的这种“溢出”将对神经网络的信息能力以及在发育过程中构建它们的机制产生深远的影响。该实验室的工作旨在确定兴奋性神经递质谷氨酸是否会溢出到海马体和视网膜的突触之间，海马体是大脑中学习和记忆存储的主要位置，视网膜则是视觉刺激编码沿视神经传输的地方。在大鼠视网膜和海马区的切片上使用电生理技术，我们发现谷氨酸从释放的突触中逃逸，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控制，谷氨酸转运蛋白主要位于神经胶质膜上，与谷氨酸结合并将其从脑脊液中移除。此外，受体神经元的电状态似乎会影响受体是否对从远处突触释放的低水平谷氨酸做出反应。正在继续研究这些机制的调制及其对神经元网络中信息处理的影响。此外，我们正在记录海马星形胶质细胞中转运蛋白介导的突触反应，以努力更定量地估计突触释放的谷氨酸从细胞外空间清除的速度。谷氨酸似乎在释放后3毫秒内被吸收，这表明它能够从其释放点扩散1-2微米。 海马区的其他研究表明，抑制性突触终末上的谷氨酸转运体为合成抑制性递质GABA提供了底物。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毒性效应可以被局部增强的抑制作用抵消。这在癫痫发作时可能特别重要。 我们在视网膜上的研究表明，在特定条件下，某些类型的受体可能会被特定地定位以限制它们的激活。在神经节细胞上，NMDA型谷氨酸受体似乎位于突触周围，因此除非同时释放许多谷氨酸小泡，否则谷氨酸转运体可以阻止它们的激活。实验室最近的工作表明，这些突触周围的受体可能会扩大神经节细胞对光刺激的反应范围。 我们同时从突触耦合的视网膜神经元进行记录的其他实验表明，带状突触能够非常快地释放递质，尽管它们的生理释放很慢。此外，我们的实验表明，在诱发反应中，带状突触协调多个囊泡的同时释放。这些结果可能为突触带的功能提供新的见解。 视网膜的其他工作探索了从A17无长突细胞到视杆双极细胞的GABA能抑制反馈。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所介导的。

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.