METABOTROPIC GLUTAMATE RECEPTORS AND BARORECEPTOR INPUT

描述（改编自申请人的摘要）：在中央 在压力感受器反射通路的网络中，压力感受器信号被整合， 快速调节动脉血压。 大部分的整合是在 孤束核（NTS），其中压力感受器信号 首先处理。 在NTS中，压力感受器信号通过 快速离子型谷氨酸受体（iGluRs）。 在高，但生理 压力感受器输入的相关频率，信号传输 郁闷. 这种频率依赖性的传播抑制早在 通路可能在更远的位置提供信息传递， 突触来优化反射功能。 仍然存在疑问的是 频率依赖性抑郁症的基础 在其他神经网络中， 慢作用G蛋白连接的代谢型谷氨酸受体（mGluR）具有 已经显示出提供快速和长期调节 iGluRs介导的神经递质传递。 这件事的焦点 研究建议mGluRs在压力感受器中的作用类似， 终末-NTS突触。 待检验的具体假设是， 压力感受器输入的频率，谷氨酸从压力感受器释放 终末，并足以激活突触后iGluRs介导 突触传递，并激活突触后mGluRs，以引起小的 缓慢的兴奋;然而，低浓度的谷氨酸释放量 频率刺激不足以激活突触前mGluRs。 作为 结果突触前mGluRs不影响突触传递。 作为 压力感受器输入频率增加，谷氨酸释放， 足够的量进一步扩散到突触间隙， 突触前mGluRs，其进一步减少谷氨酸的释放， 减少突触传递。 四个具体目标将解决这一问题 假说. 目的1利用了完整的压力反射电路在体内 为了确定NTS突触处的突触前mGluRs的激活是否 以频率依赖的方式抑制压力感受器信号传输。 目标2-4使用电压钳分析系统地隔离以下因素的作用： 突触前和突触后mGluRs对突触传递的影响 内脏输入的频率和在不同的膜电位的 突触后细胞。 预期了解mGluRs如何调节 压力感受器信号传输将促进我们对急性和 压力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.