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Cell Reports, July 20, 2021, 36(3):109417 | https://doi.org/10.1016/j.celrep.2021.109417 Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

Seungjoon Kim^1,6, Dongseok Park^1,6, Jinhu Kim^1,6,Dongwook Kim¹, Hyeonho Kim¹, Takuma Mori²,Hyeji Jung¹, Dongsu Lee³, Sookyung Hong⁴, Jongcheol Jeon⁴, Katsuhiko Tabuchi^2,5, Eunji Cheong³, Jaehoon Kim⁴, Ji Won Um^1,7,8,*and Jaewon Ko^1,7,*

¹Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea
²Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 390-86221, Japan
³Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
⁴Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
⁵Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan
⁶These authors contributed equally
⁷Senior author
⁸Lead contact

^*Correspondence

Abstract

Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally regulates the expression of IQSEC3, a GABAergic synapse-specific guanine nucleotide-exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Neuronal activation by an enriched environment induces Npas4-mediated upregulation of IQSEC3 protein specifically in CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons. SST+ interneuron-specific knockout (KO) of Npas4 compromises synaptic transmission in these GABAergic interneurons, increases neuronal activity in CA1 pyramidal neurons, and reduces anxiety behavior, all of which are normalized by the expression of wild-type IQSEC3, but not a dominant-negative ARF-GEF-inactive mutant, in SST+ interneurons of Npas4-KO mice. Our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 and ARF activity, specifically in SST+ interneurons, to orchestrate excitation-to-inhibition balance and control anxiety-like behavior.

논문정보

형식Research article
게재일2021년 07월 (BRIC 등록일 2021-07-23)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학

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