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.
