METABOTROPIC GLUTAMATE RECEPTORS AND BARORECEPTOR INPUT

描述(改编自申请人的摘要)：在中央 压力感受器通路的网络，压力感受器信号被整合到 快速调节动脉血压。大部分集成都在 孤束核(NTS)，压力感受器信号在那里 第一次处理。在NTS中，气压感受器信号由 快速离子型谷氨酸受体(IGluRs)。虽然很高，但从生理上讲 相关频率的压力感应器输入，信号传输为 情绪低落。这种频率依赖的传播抑制在早期 通路可能用于适应更远端的信息传递 突触以优化反射功能。仍然存在疑问的是这种机制 这是频率依赖性抑郁症的潜在原因。在其他神经网络中， 慢作用G蛋白相关的代谢性谷氨酸受体(MGluRs)有 已被证明可提供急性和长期的FAST调制 IGluRs介导的谷氨酸能传递。这件事的重点是 研究建议是mGluRs在压力感受器中的作用类似 终末-NTS突触。需要检验的具体假设是，在低 压力感受器输入频率，谷氨酸从压力感受器释放 终末，并足以激活突触后iGluR来调节 突触传递并激活突触后mGluR 慢兴奋；然而，谷氨酸的释放量低 频率刺激不足以激活突触前mGluRs。作为一名 结果突触前mGluR不影响突触传递。AS 压力感受器输入频率增加，谷氨酸在体内释放 足够的量扩散到突触裂隙以激活 突触前mGluRs，减少谷氨酸的进一步释放，最终 减少突触传递。四个具体目标将解决这一问题 假设。Aim 1利用体内完整的压力感受器反射回路 确定突触前mGluR在NTS突触的激活是否 以频率依赖的方式抑制压力感受器信号传输。 AIMS 2-4使用电压钳分析系统地分离 突触前后mGluR对突触传递的影响 内脏传入频率和不同膜电位 突触后细胞。预计知道mGluRs是如何调节的 压力感受器信号的传递将促进我们对急性和慢性精神分裂症的理解 可能是压力感受器反射功能的长期变化。

DESCRIPTION (Adapted from the applicant's abstract): Within the central network of the baroreflex pathway, baroreceptor signals are integrated to rapidly regulate arterial blood pressure. Much of the integration is in the nucleus of the solitary tract (NTS), where the baroreceptor signals are first processed. In the NTS, baroreceptor signals are transmitted by the fast ionotropic glutamate receptors (iGluRs). At high, yet physiologically relevant frequencies of baroreceptor input, the signal transmission is depressed. This frequency-dependent depression of transmission early in the pathway likely serves to accommodate information-transfer at more distal synapses to optimize reflex function. Still in question is the mechanism underlying the frequency-dependent depression. In other neural networks, slow-acting G protein-linked metabotropic glutamate receptors (mGluRs) have been shown to provide both acute and long-term modulation of fast glutamatergic transmission mediated by the iGluRs. The focal point of this research proposal is that mGluRs operate similarly at baroreceptor terminal-NTS synapses. The Specific Hypothesis to be tested is that at low frequencies of baroreceptor input, glutamate is released from baroreceptor terminals and is sufficient to activate postsynaptic iGluRs to mediate synaptic transmission and to activate postsynaptic mGluRs to evoke a small slow excitation; however, the amount of glutamate released with low frequency stimulation is insufficient to activate presynaptic mGluRs. As a result presynaptic mGluRs do not affect synaptic transmission. As baroreceptor input frequency is increased, glutamate is released in sufficient amounts to diffuse further into the synaptic cleft to activate presynaptic mGluRs which decreases further glutamate release and ultimately reduces synaptic transmission. Four Specific Aims will address this hypothesis. Aim 1 takes advantage of an intact baroreflex circuitry in vivo to determine whether activation of presynaptic mGluRs at NTS synapses depresses baroreceptor signal transmission in a frequency-dependent manner. Aims 2-4 use voltage clamp analysis to isolate systematically the roles of pre- and postsynaptic mGluRs on synaptic transmission at increasing frequencies of visceral input and at different membrane potentials of the postsynaptic cells. It is anticipated that knowing how mGluRs modulate baroreceptor signal transmission will advance our understanding of acute and perhaps long-term changes in baroreflex function.