title: Enhanced astroglial GABA uptake attenuates tonic GABAA inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure.
abstract: γ-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents (Itonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABAA receptors (GABAARs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of Itonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The Itonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced Itonic sensitivity to THIP argued for the decreased function of GABAAR δ subunits in HF, whereas similar Itonic sensitivity to benzodiazepines argued against the difference of γ2 subunit-containing GABAARs in SHAM and HF rats. HF Itonic 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 Itonic responses to bestrophin-1 blockade in SHAM and HF neurons further argued against a role for astroglial GABA release in HF Itonic 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 GABAARs function, the enhanced astroglial GABA uptake-induced attenuation of Itonic in HF PVN-RVLM neurons explains the deficit in tonic GABAergic inhibition and increased sympathetic outflow from the PVN during heart failure.
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea;
authors.forename: Sudip
authors.initials: S
authors.lastname: Pandit
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea;
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Jo
authors.affiliation: Department of Anesthesiology and Pain Medicine, Brain Research Institute, School of Medicine, Chungnam National University, Daejeon, Republic of Korea; and.
authors.forename: Sang Ung
authors.initials: SU
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology and Pain Medicine, Brain Research Institute, School of Medicine, Chungnam National University, Daejeon, Republic of Korea; and.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute of Veterinary Science, Seoul National University, Seoul, Republic of Korea.
authors.forename: So Yeong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute of Veterinary Science, Seoul National University, Seoul, Republic of Korea.
authors.forename: Pan Dong
authors.initials: PD
authors.lastname: Ryu
authors.affiliation: Department of Anesthesiology and Pain Medicine, Brain Research Institute, School of Medicine, Chungnam National University, Daejeon, Republic of Korea; and.
authors.forename: Jung Un
authors.initials: JU
authors.lastname: Lee
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea;
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea;
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea; jinbong@cnu.ac.kr.
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000503:physiopathology; D009203:Myocardial Infarction / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid
keywords: GABA transporters; heart failure; sympathetic outflow; tonic GABAA inhibition