IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus

长时程增强 神经科学 海马结构 海马体 突触 加巴能 生物 树突棘 神经传递 条件基因敲除 细胞生物学 抑制性突触后电位 受体 生物化学 表型 基因
作者
Dong‐Wook Kim,Hyeji Jung,Yoshinori Shirai,Hyeonho Kim,Jinhu Kim,Dongseok Lim,Takuma Mori,Hyojeong Lee,Dongseok Park,Hee Young Kim,Guo Qi,Bo Pang,Wen Qiu,Xueshan Cao,Emi Kouyama-Suzuki,Takeshi Uemura,Enas A. Kasem,Yu Fu,Seungjoon Kim,Akinori Tokunaga,Takahiro Yoshizawa,Tatsuo Suzuki,Hiroyuki Sakagami,Kea Joo Lee,Jaewon Ko,Katsuhiko Tabuchi,Ji Won Um
出处
期刊:Biological Psychiatry [Elsevier BV]
卷期号:91 (9): 821-831 被引量:7
标识
DOI:10.1016/j.biopsych.2021.12.016
摘要

IQSEC3, a gephyrin-binding GABAergic (gamma-aminobutyric acidergic) synapse-specific guanine nucleotide exchange factor, was recently reported to regulate activity-dependent GABAergic synapse maturation, but the underlying signaling mechanisms remain incompletely understood.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 used to address our question.We found that Iqsec3-cKO induces a specific reduction in GABAergic synapse density, GABAergic synaptic transmission, and maintenance of long-term potentiation 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-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 long-term potentiation maintenance. Finally, upregulated S6K1 signaling was rescued by IQSEC3 wild-type, but not by an ARF-GEF (adenosine diphosphate ribosylation factor-guanine nucleotide exchange factor) inactive IQSEC3 mutant.Our results suggest that IQSEC3-mediated balanced synaptic inhibition in hippocampal CA1 is critical for the proper formation of hippocampus-dependent fear memory.
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