Heterosynaptic crosstalk: GABA-glutamate metabotropic receptors interactively control glutamate release in solitary tract nucleus

Synaptic terminals often contain metabotropic receptors that act as autoreceptors to control neurotransmitter release. Less appreciated is the heterosynaptic crossover of glutamate receptors to control GABA release and vice versa GABA receptors which control glutamate release. In the brainstem, activation of solitary tract (ST) afferents releases glutamate onto second-order neurons within the solitary tract nucleus (NTS). Multiple metabotropic receptors are expressed in NTS for glutamate (mGluRs) and for GABA (GABAB). The present report identifies mGluR regulation of glutamate release at second and higher order sensory neurons in NTS slices. We found strong inhibition of glutamate release to group II and III mGluR activation on mechanically isolated NTS neurons. However, the same mGluR-selective antagonists paradoxically decreased glutamate release (miniature, mEPSCs) at identified second-order NTS neurons. Unaltered amplitudes were consistent with selective presynaptic mGluR actions. GABAB blockade in slices resolved the paradoxical differences and revealed a group II/III mGluR negative feedback of mEPSC frequency similar to isolated neurons. Thus, the balance of glutamate control is tipped by mGluR receptors on GABA terminals resulting in predominating heterosynaptic GABAB inhibition of glutamate release. Regulation by mGluR or GABAB was not consistently evident in excitatory postsynaptic currents (EPSCs) in higher-order NTS neurons demonstrating metabotropic receptor distinctions in processing at different NTS pathway stages. These cellular localizations may figure importantly in understanding interventions such as brain-penetrant compounds or microinjections. We conclude that afferent glutamate release in NTS produces a coordinate presynaptic activation of co-localized mGluR and GABAB feedback on cranial afferent terminals to regulate glutamate release.

Research Highlights▶The presence of mGluR II/III on both glutamate and GABA terminals at solitary tract neurons (NTS) obscured mGluR responses by triggered GABA release via GABAB receptors controlling glutamate. ▶GABAB receptors are present on glutamate terminals at both second- and higher order NTS neurons but mGluR II/III are present only at second-order neurons. ▶Solitary tract glutamate release is differently controlled than other glutamate release in NTS. ▶No functioning presynaptic mGlurR I was found.