Metabotropic Glutamate Receptors and Baroreceptor Input

描述(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谷氨酸作用于离子型谷氨酸受体而从初级纤维传递到NTS的二级神经元，但正是抑制和兴奋机制的平衡决定了NTS的输出，而NTS的输出又协调了反射输出。代谢性谷氨酸受体(MGluRs)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，使其能够通过全面的突触前和突触后机制调节自身的信号。我们的长期目标是研究mGluRs如何以及何时以尖锐和长期的方式塑造压力感受器信号的NTS输出。在我们的父母资助中，我们发现在高频压力感受器放电过程中释放的谷氨酸激活了中央终末上的突触前mGluRs，以减少谷氨酸的释放，精确地调节到达二级神经元的数量。这一新的研究以突触前和突触后mGluR效应的新发现为特色：1)高频压力感受器放电时释放的谷氨酸到达附近GABA终末的突触前mGluR以抑制GABA的释放，从而抑制二级神经元的GABA和谷氨酸的释放；2)突触前mGluR诱导长时间(1小时)GABA释放的变化，这是一个有希望的长期调节机制；3)突触后mGluR的激活是电压依赖的，这表明神经元的兴奋性指定了突触后mGluR对压力感受器信号的贡献；以及4)突触后mGluR诱导的神经元兴奋性的增加可能是通过几个离子电流介导的，提供了新的潜在调节部位。在这些数据的基础上，我们开发了六个AIMS，以检验以下假设：1.突触前mGluRs通过抑制二阶NTS压力感受器神经元上谷氨酸和GABA的释放来调节压力感受器信号的传递，这种调制对突触的兴奋性产生短期和长期影响(AIMS 1-3)；以及2.突触后mGluRs通过调节多个离子电流，将固有的兴奋性和突触的兴奋性结合起来，形成短期和长期的压力感受器信号(AIMS 4-6)。这些目的将通过使用膜片钳分析来分离在解剖和电生理识别的压力感受器二级NTS神经元上的突触前和突触后mGluR效应。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的急性和长期调节提供新的机制，从而为压力感受性反射功能的调节提供新的机制。

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.