Metabotropic Glutamate Receptors and Baroreceptor Input

代谢型谷氨酸受体和压力感受器输入

• 批准号: 6845970
• 负责人: ANN C. BONHAM
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845970
• 关键词: baroreceptors; baroreflex; electrical potential; electrophysiology; gamma aminobutyrate; glutamate receptor; glutamates; laboratory rat; membrane potentials; neural transmission; solitary tract nucleus; synapses; voltage /patch clamp

DESCRIPTION (provided by applicant): The nucleus tractus solitarius (NTS) is a key regulatory moment in baroreceptor reflex control of blood pressure. The baroreceptor signals are transmitted from the primary fibers to the second-order NTS neurons by glutamate acting at ionotropic glutamate receptors, but it is the balance of inhibitory and excitatory mechanisms modulating this transmission that determines the NTS output, which in turn, orchestrates reflex output. The metabotropic glutamate receptors (mGluRs) have expanded the classic neurotransmitter role of glutamate to an extensive neuromodulator role by allowing it to regulate it's own signaling through comprehensive presynaptic and postsynaptic mechanisms. Our long-term goal is to characterize how and when mGluRs shape NTS output of baroreceptor signals acutely and long-term. In our parent grant, we showed that glutamate released during high frequency baroreceptor firing activated presynaptic mGluRs on the central terminals to decrease glutamate release, precisely regulating the amount reaching the second-order neurons. This renewal features new findings on presynaptic and postsynaptic mGluR effects: 1) glutamate released during high-frequency baroreceptor firing reaches presynaptic mGluRs on nearby GABA terminals to depress GABA release, thereby depressing both GABA and glutamate release at the second-order neurons; 2) presynaptic mGluRs induce long-term (1 hr) changes in GABA release, a promising mechanism for long-term regulation; 3) postsynaptic mGluR activation is voltage dependent, suggesting that the neuronal excitability specifies the postsynaptic mGluR contribution to baroreceptor signaling; and 4) postsynaptic mGluR-induced increases in neuronal excitability may be mediated via several ionic currents, providing new potential regulatory sites. Building on these data, we developed six Aims, to test the Hypotheses that: 1. presynaptic mGluRs modulate baroreceptor signal transmission at NTS baroreceptor synapses by inhibiting both glutamate and GABA release onto second-order NTS baroreceptor neurons, a modulation that exerts both short- and long-term effects on synaptic excitability (Aims 1-3); and 2. postsynaptic mGluRs on these same neurons, by modulating multiple ionic currents, integrate the intrinsic excitability with synaptic excitability to shape short- and long-term baroreceptor signaling (Aims 4-6). The Aims will be achieved by using patch-clamp analysis to isolate presynaptic and postsynaptic mGluR effects on anatomically- and electrophysiologically-identified baroreceptor second-order NTS neurons in a slice. Understanding precisely how and when mGluRs modulate synaptic and intrinsic excitability at these NTS synapses will provide new mechanisms for the acute and long-term regulation of baroreceptor signaling and hence baroreflex function.

描述（由申请人提供）：孤束核（NTS）是压力感受器反射控制血压的关键调节时刻。压力感受器信号通过作用于离子型谷氨酸受体的谷氨酸从初级纤维传输到二级 NTS 神经元，但调节这种传输的抑制和兴奋机制的平衡决定了 NTS 输出，进而协调反射输出。代谢型谷氨酸受体 (mGluR) 允许谷氨酸通过全面的突触前和突触后机制调节其自身的信号传导，从而将谷氨酸的经典神经递质作用扩展到广泛的神经调节剂作用。我们的长期目标是表征 mGluR 如何以及何时敏锐且长期地塑造压力感受器信号的 NTS 输出。在我们的资助中，我们发现高频压力感受器放电过程中释放的谷氨酸会激活中央末端的突触前 mGluR，以减少谷氨酸的释放，从而精确调节到达二级神经元的量。这一更新的特点是关于突触前和突触后 mGluR 效应的新发现：1）高频压力感受器放电过程中释放的谷氨酸到达附近 GABA 末端的突触前 mGluR，抑制 GABA 释放，从而抑制二级神经元的 GABA 和谷氨酸释放； 2) 突触前 mGluR 诱导 GABA 释放的长期（1 小时）变化，这是一种有前景的长期调节机制； 3) 突触后 mGluR 激活是电压依赖性的，这表明神经元兴奋性指定了突触后 mGluR 对压力感受器信号传导的贡献； 4) 突触后 mGluR 诱导的神经元兴奋性增加可能是通过几种离子电流介导的，从而提供了新的潜在调节位点。基于这些数据，我们制定了六个目标，以测试以下假设： 1. 突触前 mGluR 通过抑制谷氨酸和 GABA 释放到二级 NTS 压力感受器神经元上来调节 NTS 压力感受器突触的压力感受器信号传递，这种调节同时发挥短-以及对突触兴奋性的长期影响（目标 1-3）； 2. 这些相同神经元上的突触后 mGluR，通过调节多个离子电流，将内在兴奋性与突触兴奋性整合起来，形成短期和长期压力感受器信号传导（目标 4-6）。该目标将通过使用膜片钳分析分离突触前和突触后 mGluR 对切片中解剖学和电生理学识别的压力感受器二阶 NTS 神经元的影响来实现。准确了解 mGluRs 如何以及何时调节这些 NTS 突触的突触和内在兴奋性将为压力感受器信号传导以及压力感受反射功能的急性和长期调节提供新机制。