Metabotropic Glutamate Receptors and Baroreceptor Input

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递到二级NTS神经元，但调节这种传递的抑制和兴奋机制的平衡决定了NTS输出，反过来，协调反射输出。代谢型谷氨酸受体（mGluRs）通过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，将谷氨酸的经典神经递质作用扩展为广泛的神经调节剂作用。我们的长期目标是表征mGluRs如何以及何时形成NTS压力感受器信号的急性和长期输出。在我们的研究中，我们发现在高频率压力感受器放电过程中释放的谷氨酸激活了中枢末梢上的突触前mGluRs，以减少谷氨酸的释放，精确地调节到达二级神经元的量。这一更新的特点是对突触前和突触后mGluR效应的新发现：1）在高频压力感受器放电过程中释放的谷氨酸到达突触前mGluR附近的GABA终末以抑制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，这是一种有希望的长期调节机制; 3）突触后mGluR激活是电压依赖性的，表明神经元兴奋性指定突触后mGluR对压力感受器信号传导的贡献;和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，提供新的潜在调节位点。在这些数据的基础上，我们开发了六个目标，以验证假设：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压力感受器突触处的压力感受器信号传递，这是一种对突触兴奋性发挥短期和长期作用的调节（目的1-3）;和2.通过调节多个离子电流，这些相同神经元上的突触后mGluR整合内在兴奋性与突触兴奋性以形成短期和长期压力感受器信号传导（目的4-6）。将通过使用膜片钳分析来分离突触前和突触后mGluR对切片中解剖学和电生理学鉴定的压力感受器二级NTS神经元的影响来实现目的。精确地了解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的急性和长期调节以及压力反射功能提供新的机制。

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.