Enhanced astroglial GABA uptake attenuates tonic GABAA inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure

gamma-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents (I-tonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABA(A) receptors (GABA(A)Rs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of I-tonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The I tonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced I tonic sensitivity to THIP argued for the decreased function of GABA(A)R delta subunits in HF, whereas similar I-tonic sensitivity to benzodiazepines argued against the difference of gamma(2) subunit-containing GABA(A)Rs in SHAM and HF rats. HF I-tonic attenuation was reversed by a nonselective GABA transporter (GAT) blocker (nipecotic acid, NPA) and a GAT-3 selective blocker, but not by a GAT-1 blocker, suggesting that astroglial GABA clearance increased in HF. Similar and minimal I-tonic responses to bestrophin-1 blockade in SHAM and HF neurons further argued against a role for astroglial GABA release in HF I-tonic attenuation. Finally, the NPA-induced inhibition of spontaneous firing was greater in HF than in SHAM PVN-RVLM neurons, whereas diazepam induced less inhibition of spontaneous firing in HF than in SHAM neurons. Overall, our results showed that combined with reduced GABA(A)Rs function, the enhanced astroglial GABA uptake-induced attenuation of I-tonic in HF PVN-RVLM neurons explains the deficit in tonic GABAergic inhibition and increased sympathetic outflow from the PVN during heart failure.