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: 6727135
• 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/6727135
• 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）：Tractus solitarius（NTS）是压力感受器反射对血压的关键调节时刻。压力感受器信号通过谷氨酸在离子型谷氨酸受体上作用从主要纤维从主要纤维传播到二阶NTS神经元，但它是调节这种透射透射的抑制性和兴奋机制的平衡，从而决定了NTS输出，这反过来旋转反射输出。代谢性谷氨酸受体（MGLURS）通过允许其通过全面的突触前和突触后机制来调节其自身的信号传导，从而扩展了谷氨酸的经典神经递质作用。我们的长期目标是表征mglurs如何和何时塑造压力感受器信号的NTS输出，急性和长期。在我们的父授予中，我们表明，在高频压力受体发射中释放的谷氨酸在中央末端激活了突触前的mglurs，以减少谷氨酸释放，从而精确调节达到二阶神经元的量。这种续签以突触前和突触后的mglur效果为特征：1）在高频压力受体射击中释放的谷氨酸释放，触发在附近的GABA终端上突触前mglurs降低GABA的释放，从而使Gaba和Glutamate释放抑制Gaba和Glutamate释放。 2）突触前mglurs在GABA释放中诱导长期变化（1小时），这是长期调节的有前途的机制； 3）突触后MGLUR激活取决于电压，这表明神经元兴奋性指定突触后MGLUR对压力感受器信号的贡献； 4）突触后MGLUR诱导的神经元兴奋性增加可以通过几种离子电流介导，从而提供新的潜在调节位点。 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);和2。通过调节多种离子电流的这些相同神经元上的突触后mglurs，将内在的兴奋性与突触兴奋性整合在一起，以形成短期和长期的压力感受器信号传导（AIMS 4-6）。将通过使用斑块夹分析分离出对解剖学上和电生理学的压力受体受体二阶NTS神经元的突触前和突触后MGLUR作用来实现目标。精确地了解这些NTS突触的MGLUR如何以及何时调节突触和内在的兴奋性，将为压力感受器信号传导的急性和长期调节提供新的机制，从而为BaroreFlex功能提供了新的机制。