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

Abstract

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 μm) caused a large increase in GABA A I tonic , and reduced IPSC frequency. These effects were replicated by β-alanine (100 μm), but not by SKF 89976A (30 μm), relatively selective blockers of GAT3 and GAT1 isoforms, respectively. Similar effects were evoked by the gliotoxin l-α-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.

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

“…Astrocytes are closely involved in the control of the biosynthesis and turnover of glutamate and GABA, and regulate neural function via the release of glutamate, ATP, and other signaling molecules (8,40). Moreover, GABA-transporters expressed in astrocytes contribute to GABA tone in various neural circuits, and astrocytes regulate sympathetic outflow (36). Although the role of astrocytes in heart failure has not been examined until recently, a very recent report suggests that the actions of ATP derived from astrocytes within the RVLM contribute to increase sympathetic outflow and facilitate LV remodeling (31).…”

Role of small conductance calcium-activated potassium channels expressed in PVN in regulating sympathetic nerve activity and arterial blood pressure in rats

“…Evidence for this is shown in PVN neurotransmitter systems that include GABA (30,38), glutamate (9,28,31), nitric oxide (4,20), and ANG II (7,13,29), which modulate the activity of presympathetic PVN neurons in vitro and SNA in vivo. One class of channels likely to play a role in this effect are small conductance Ca 2ϩ -activated K ϩ (SK) channels that control excitability of neurons.…”

Effects of valproic acid on sympathetic activity and left ventricularmyocardial remodelling in rats during pressure overload

“…The role of the hypothalamus in nerve action relies on many neurotransmitters, including glutamic acid and GABA. Modulating ambient GABA levels or the efficacy of GABAergic synaptic inputs in the hypothalamic pressor area tonically inhibits sympathetic outflow and arterial blood pressure (34)(35)(36). Therefore, regulation of GABA levels in the hypothalamus might be a potential target for inhibiting sympathetic outflow.…”