POSTSYNAPTIC FACTORS AFFECTING SYNAPTIC EFFICACY IN VIVO

我们的长期目标是确定 中枢性突触，特别是突触后膜的特性 它们影响突触传递的有效性和时程，并 这也可能为神经元的可塑性提供底物。意义重大 突触后特性包括递质-受体参数 相互作用，应为合理药物的开发提供基础 治疗方法和结构参数。后者包括受体或 突触和突触外基因的结合位点密度以及 突触间隙、突触后受体矩阵和 突触接触区。这些结构参数中的许多都在 病理状态，如重症肌无力，以及由于 经历或神经对损伤的反应。尽管如此，没有 全面的模型，使我们能够解释这些结果 神经功能的结构改变。拟议的研究是 旨在研究中央甘氨酸能连接的组织，通过 一种已鉴定脊椎动物中枢抑制反应的研究 神经元，金鱼的莫特纳细胞，并开发了一个计算机模型 回应。具体目标包括1)电生理分析 甘氨酸激活通道和量子抑制通道的性质 体内反应，以及2)关于诱发的效应是否介导的研究 甘氨酸的释放受到扩散或摄取/失活的限制 机械装置。此外，利用士的宁拮抗作用的初步数据 甘氨酸介导的反应导致了相邻的假设 相同或不同传入的突触前终末可能具有 重叠的突触后区域。第三(3)个特定目标是测试这一点 假说，通过研究电压钳制技术，相互作用 突触后对激活不同单个神经元或 一簇簇突触前神经元。电生理实验将 涉及Mauthner细胞的电压钳，活体内。最后，第四个目标 就是用实验数据来检验和加强计算机模型 提供了一个具体的理解基础 不同结构参数所发挥的功能作用 更改这些参数的影响。

Our long-term objectives are to determine the principles of operation of central synapses, particularly the properties of postsynaptic membranes which influence the efficacy and time course of synaptic transmission and which also might provide substrates for neuronal plasticity. Significant postsynaptic properties include the parameters of transmitter-receptor interactions, which should provide a basis for development of rational drug therapies, and structural parameters. The latter include receptor or binding site densities at synaptic and extra-synaptic loci and the dimensions of the synaptic cleft, the postsynaptic receptor matrix, and the synaptic contact zone. Many of these structural parameters are altered in pathological conditions, such as in myasthenia gravis, and as a result of experience or neuronal responses to injury. Nevertheless, there is no comprehensive model which allows us to interpret the consequences of these structural modifications for neuronal function. The proposed research is designed to study the organization of a central glycinergic junction, by studying the inhibitory responses of an identified vertebrate central neuron, the goldfish Mauthner cell, and to develop a computer model of the responses. Specific aims include 1) an electrophysiological analysis of the properties of the glycine activated channels and of quantal inhibitory responses in vivo, and 2) a study of whether the effects mediated by evoked glycine release are limited by diffusion or uptake/inactivation mechanisms. In addition, preliminary data utilizing strychnine antagonism of glycine mediated responses has led to the hypothesis that adjacent presynaptic terminals of the same or different afferents may have overlapping postsynaptic domains. A third (3) specific aim is to test this hypothesis by studying, with voltage clamp techniques, the interactions of postsynaptic responses to activation of different individual neurons or of clusters of presynaptic neurons. The electrophysiological experiments will involve voltage clamp of the Mauthner cell, in vivo. finally, a fourth aim is to use the experimental data to test and strengthen the computer model of quantal responses, to provide a concrete foundation for understanding the functional roles exerted by different structural parameters and the effects of altering these parameters.