The nucleus tractus solitarii (NTS) is essential for coordinating arterial baroreflex control of blood pressure. The primary baroreceptor afferent fibres make their first excitatory synaptic contact at second-order NTS neurones with glutamate as the major neurotransmitter. Glutamate regulates its own release by activating presynaptic metabotropic glutamate autoreceptors (mGluRs) on the baroreceptor central terminals to suppress its further release in frequency-dependent manner. γ-Aminobutyric acid (GABA) interneurones provide the major inhibitory synaptic input. It is the integration of excitatory and inhibitory inputs that shapes the NTS output of baroreceptor signals. We hypothesized that glutamate released from the primary central afferent terminals can spill over to presynaptic mGluRs on GABA interneurones to suppress GABA release at the second-order baroreceptor neurones. We assessed GABA transmission in second-order baroreceptor neurones identified by attached aortic depressor nerve (ADN) boutons. The medial NTS was stimulated to evoke GABA inhibitory post-synaptic currents (eIPSCs). Glutamate spillover, generated by brief 2 s, 25 Hz trains of stimuli applied to the tractus solitarius (TS), induced a small (10%) but significant reduction in the eIPSC amplitudes. The depression was enhanced to a 25% decrease by increasing glutamate in the cleft with a glutamate-uptake inhibitor (M-trans-pyrrolidine-2,4-dicarboxylic acid, 1 μM), blocked by a Group II mGluR antagonist (LY341495, 200 nM) and mimicked by a Group II agonist ((2S,3S,4S)-CCG/(2S,1′S,2′S-2-carboxycyclopropyl; L-CCG-I). A presynaptic mGluR locus was established by the mGluR agonist-mediated increase in the paired-pulse ratio of two consecutive eIPSCs in conjunction with the decrease in the first eIPSC, and a decrease in the frequency (39-46% reduction at EC50 concentration), but not amplitude, of spontaneous and miniature GABA IPSCs. The data indicate that endogenous glutamate activation of Group II presynaptic mGluRs can decrease GABA release at the first central synapses, suggesting a heterosynaptic role for the Group II mGluRs in shaping baroreceptor signal transmission.
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