한빛사논문
- 조회1,149
Dongwook Kim1,#, Hyeji Jung1,#, Yoshinori Shirai2,#, Hyeonho Kim1, Jinhu Kim1, Dongseok Lim1, Takuma Mori2,3, Hyojeong Lee1, Dongseok Park1, Hee Young Kim1, Qi Guo2, Bo Pang2, Wen Qiu2, Xueshan Cao2, Emi Kouyama-Suzuki2, Takeshi Uemura2, Enas Kasem2,4, Yu Fu2, Seungjoon Kim1, Akinori Tokunaga5, Takahiro Yoshizawa6, Tatsuo Suzuki2, Hiroyuki Sakagami7, Kea Joo Lee1,8, Jaewon Ko1, Katsuhiko Tabuchi2,3,*, Ji Won Um1,*
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
2Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan
3Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan
4Department of Zoology, Faculty of Science, Kafrelsheikh University, 33511 Kafrelsheikh, Egypt
5Division of Laboratory Animal Resources, Life Science Research Laboratory, University of Fukui, 23-3 Matsuoka, Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 9101193 Japan
6Research Center for Supports to Advanced Science, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan
7Department of Anatomy, Kitasato University School of Medicine, 1-15-1, Kitazato, Minami, Sagamihara, Kanagawa 252-0374, Japan
8Neural Circuits Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Korea
#These authors contributed equally: Dongwook Kim, Hyeji Jung, Yoshinori Shirai
*Corresponding author.
Abstract
Background
IQSEC3, a gephyrin-binding GABAergic synapse-specific guanine nucleotide exchange factor, was recently reported to regulate activity-dependent GABAergic synapse maturation, but the underlying signaling mechanisms remain incompletely understood.
Methods
We generated mice with conditional knockout (cKO) of Iqsec3 to examine whether altered synaptic inhibition influences hippocampus-dependent fear memory formation. In addition, electrophysiological recordings, immunohistochemistry, and behavioral assays were employed to address our question.
Results
We found that Iqsec3-cKO induces a specific reduction in GABAergic synapse density, GABAergic synaptic transmission, and maintenance of long-term potentiation (LTP) in the hippocampal CA1 region. In addition, Iqsec3-cKO mice exhibited impaired fear memory formation. Strikingly, Iqsec3-cKO caused abnormally enhanced activation of ribosomal P70-S6 kinase1 (S6K1)-mediated signaling in the hippocampus, but not in the cortex. Furthermore, inhibiting upregulated S6K1 signaling by expressing dominant-negative S6K1 in the hippocampal CA1 of Iqsec3-cKO mice completely rescued impaired fear learning and inhibitory synapse density, but not deficits in LTP maintenance. Lastly, upregulated S6K1 signaling was rescued by IQSEC3 wild-type, but not by an ARF-GEF inactive IQSEC3 mutant.
Conclusions
Our results suggest that IQSEC3-mediated balanced synaptic inhibition in the hippocampal CA1 is critical for proper formation of hippocampus-dependent fear memory.
논문정보
- Research article
- 2021년 12월 (BRIC 등록일 2022-01-10)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
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