Regulation of tonic GABA inhibitory function, presympathetic neuronal activity and sympathetic outflow from the paraventricular nucleus by astroglial GABA transporters.

摘要

Neuronal activity in the hypothalamic paraventricular nucleus (PVN), as well as sympathetic outflow from the PVN, is basally restrained by a GABAergic inhibitory tone. We recently showed that two complementary GABA(A) receptor-mediated modalities underlie inhibition of PVN neuronal activity: a synaptic, quantal inhibitory modality (IPSCs, I(phasic)) and a sustained, non-inactivating modality (I(tonic)). Here, we investigated the role of neuronal and/or glial GABA transporters (GATs) in modulating these inhibitory modalities, and assessed their impact on the activity of RVLM-projecting PVN neurons (PVN-RVLM neurons), and on PVN influence of renal sympathetic nerve activity (RSNA). Patch-clamp recordings were obtained from retrogradely labelled PVN-RVLM neurons in a slice preparation. The non-selective GAT blocker nipecotic acid (100-300 microM) caused a large increase in GABA(A)I(tonic), and reduced IPSC frequency. These effects were replicated by beta-alanine (100 microM), but not by SKF 89976A (30 microM), relatively selective blockers of GAT3 and GAT1 isoforms, respectively. Similar effects were evoked by the gliotoxin L-alpha-aminodipic acid (2 mM). GAT blockade attenuated the firing activity of PVN-RVLM neurons. Moreover, PVN microinjections of nipecotic acid in the whole animal diminished ongoing RSNA. A robust GAT3 immunoreactivity was observed in the PVN, which partially colocalized with the glial marker GFAP. Altogether, our results indicate that by modulating ambient GABA levels and the efficacy of GABA(A)I(tonic), PVN GATs, of a likely glial location, contribute to setting a basal tone of PVN-RVLM firing activity, and PVN-driven RSNA.