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

Abstract

Park JB. Enhanced astroglial GABA uptake attenuates tonic GABA A inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure. J Neurophysiol 114: 914 -926, 2015. First published June 10, 2015 doi:10.1152/jn.00080.2015.-␥-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 ␦ subunits in HF, whereas similar I tonic sensitivity to benzodiazepines argued against the difference of ␥ 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.

Balancing tonic and phasic inhibition in hypothalamic corticotropin‐releasing hormone neurons

“…, ; Pandit et al . ). Additionally, presynaptic GABA B Rs, which decrease release probability ( P r ) of GABA, are also present within the PVN (Liu et al .…”

“…Since the high-affinity GABA A Rs responsible for I Tonic reside in extrasynaptic regions (Rossi & Hamann, 1998;Lee et al 2014), mechanisms that control both the concentration of GABA and its access to extra-and perisynaptic regions will impact the balance between I Tonic and I Phasic . GABA transporters (GATs) in astrocytes and neurons play a key role in constraining I Tonic in other cell populations in PVN (Park et al 2006(Park et al , 2009Pandit et al 2015). Additionally, presynaptic GABA B Rs, which decrease release probability (P r ) of GABA, are also present within the PVN (Liu et al 2006;Gao et al 2017).…”

Systemic Sympathoexcitation Was Associated with Paraventricular Hypothalamic Phosphorylation of Synaptic CaMKIIα and MAPK/ErK

“…The PVN has initially been described as a mere relay station for neurons of the descending hypothalamic-hypophysial systems (Babović et al, 2009 ). However, morphological and electrophysiological characterization of PVN neurons shows that it is made up of several integrated excitatory and inhibitory neural circuits concerned with the regulation of autonomic cardiovascular functions (Pyner, 2009 ; Glass et al, 2015 ; Pandit et al, 2015 ; Ogundele et al, 2016a ). An important component of the pre-autonomic sympathetic control is the activity of adrenergic neurotransmitters in parts of the brain connected to the PVN (Jung et al, 2004 ).…”

The anti-inflammatory role of extranuclear apurinic/apyrimidinic endonuclease 1/redox effector factor-1 in reactive astrocytes

“…Sections (25 μm) from post-fixed brains in 4% paraformaldehyde were cut using a cryostat as described previously [56]. Free-floating sections subjected to immunohistochemical staining using the avidin-biotin peroxidase complex (ABC) method were incubated with primary anti-APE1/Ref-1 (1:200 dilution).…”