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Exp Neurobiol 2022; 31(3): 147-157
Published online June 30, 2022
https://doi.org/10.5607/en22014
© The Korean Society for Brain and Neural Sciences
Moonsun Sa1,2, Jung Moo Lee1,2, Mingu Gordon Park1,2, Jiwoon Lim2,3, Jong Min Joseph Kim4, Wuhyun Koh2, Bo-Eun Yoon4 and C. Justin Lee1,2,3*
1KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, 2Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34126, 3IBS School, University of Science and Technology (UST), Daejeon 34126, 4Department of Molecular Biology, Dankook University, Cheonan 31116, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 82-42-878-9150, FAX: 82-42-878-9151
e-mail: cjl@ibs.re.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The principal inhibitory transmitter, γ-aminobutyric acid (GABA), is critical for maintaining hypothalamic homeostasis and released from neurons phasically, as well as from astrocytes tonically. Although astrocytes in the arcuate nucleus (ARC) of the hypothalamus are shown to transform into reactive astrocytes, the tonic inhibition by astrocytic GABA has not been adequately investigated in diet-induced obesity (DIO). Here, we investigated the expression of monoamine oxidase-B (MAOB), a GABA-synthesizing enzyme, in reactive astrocytes in obese mice. We observed that a chronic high-fat diet (HFD) significantly increased astrocytic MAOB and cellular GABA content, along with enhanced hypertrophy of astrocytes in the ARC. Unexpectedly, we found that the level of tonic GABA was unaltered in chronic HFD mice using whole-cell patch-clamp recordings in the ARC. Furthermore, the GABA-induced current was increased with elevated GABAA receptor α5 (GABRA5) expression. Surprisingly, we found that a nonselective GABA transporter (GAT) inhibitor, nipecotic acid (NPA)-induced current was significantly increased in chronic HFD mice. We observed that GAT1 inhibitor, NO711-induced current was significantly increased, whereas GAT3 inhibitor, SNAP5114-induced current was not altered. The unexpected unaltered tonic inhibition was due to an increase of GABA clearance in the ARC by neuronal GAT1 rather than astrocytic GAT3. These results imply that increased astrocytic GABA synthesis and neuronal GABAA receptor were compensated by GABA clearance, resulting in unaltered tonic GABA inhibition in the ARC of the hypothalamus in obese mice. Taken together, GABA-related molecular pathways in the ARC dynamically regulate the tonic inhibition to maintain hypothalamic homeostasis against the HFD challenge.
Keywords: Astrocyte, Arcuate nucleus, GABA transporter, High fat diet, Obesity, Tonic GABA