Within the central network of the baroreflex pathway, baroreceptor signals are integrated to rapidly regulate arterial blood pressure. Much of the integration is in the nucleus of the solitary tract (NTS), where the baroreceptor signals are first processed. In the NTS, baroreceptor signals are transmitted by the fast ionotropic glutamate receptors (iGluRs). At high, yet physiologically relevant frequencies of baroreceptor input, the signal transmission is depressed. This frequency-dependent depression of transmission early in the pathway likely serves to accommodate information-transfer at more distal synapses to optimize reflex function. Still in question is the mechanism underlying the frequency-dependent depression. In other neural networks, slow-acting G protein-linked metabotropic glutamate receptors (mGluRs) have been shown to provide both acute and long-term modulation of fast glutamatergic transmission mediated by the iGluRs. The focal point of this research proposal is that mGluRs operate similarly at baroreceptor terminal-NTS synapses. The Specific Hypothesis to be tested is that at low frequencies of baroreceptor input, glutamate is released from baroreceptor terminals and is sufficient to activate postsynaptic iGluRs to mediate synaptic transmission and to activate postsynaptic mGluRs to evoke a small slow excitation; however, the amount of glutamate released with low frequency stimulation is insufficient to activate presynaptic mGluRs. As a result presynaptic mGluRs do not affect synaptic transmission. As baroreceptor input frequency is increased, glutamate is released in sufficient amounts to diffuse further into the synaptic cleft to activate presynaptic mGluRs which decreases further glutamate release and ultimately reduces synaptic transmission.
Four Specific Aims will address this hypothesis.
Aim 1 takes advantage of an intact baroreflex circuitry in vivo to determine whether activation of presynaptic mGluRs at NTS synapses depresses baroreceptor signal transmission in a frequency-dependent manner.
Aims 2 -4 use voltage clamp analysis to isolate systematically the roles of pre- and postsynaptic mGluRs on synaptic transmission at increasing frequencies of visceral input and at different membrane potentials of the postsynaptic cells. It is anticipated that knowing how mGluRs modulate baroreceptor signal transmission will advance our understanding of acute and perhaps long-term changes in baroreflex function.
