IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus
IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus
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DOI：
10.1016/j.biopsych.2021.12.016
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发表时间：
2022-04-11
影响因子：
10.6
通讯作者：
Um, Ji Won
中科院分区：
文献类型：
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作者：
Kim, Dongwook;Jung, Hyeji;Um, Ji Won
背景：IQSEC3是一种与Gb结合的GABA能(γ-氨基丁酸能)突触特异性的鸟嘌呤核苷酸交换因子，最近被报道调节活性依赖的GABA能突触成熟，但其潜在的信号机制仍不完全清楚。方法：我们建立了Iqsec3条件基因敲除(CKO)的小鼠，以检查突触抑制改变是否影响海马区依赖的恐惧记忆的形成。此外，电生理记录、免疫组织化学和行为分析也被用来回答我们的问题。结果：我们发现Iqsec3-CKO能特异性地降低海马CA1区GABA能突触密度、GABA能突触传递和维持长时程增强。此外，Iqsec3-CKO小鼠表现出恐惧记忆形成障碍。值得注意的是，Iqsec3-CKO导致核糖体P70-S6K1介导的信号在海马区异常增强，但在大脑皮层没有。此外，通过在Iqsec3-CKO小鼠的海马区CA1表达显性负S6K1来抑制S6K1信号的上调，完全挽救了受损的恐惧学习和抑制性突触密度，但不影响长期增强维持。最后，上调的S6K1信号被IQSEC3野生型拯救，但不被ARF-Global(腺苷二磷酸核糖基化因子-鸟嘌呤核苷酸交换因子)失活的IQSEC3突变体拯救。结论：IQSEC3介导的海马CA1区平衡突触抑制对正常形成海马依赖的恐惧记忆至关重要。
BACKGROUND: 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. METHODS: We generated mice with conditional knockout (cKO) of Iqsec3 to examine whether altered synaptic in-hibition influences hippocampus-dependent fear memory formation. In addition, electrophysiological recordings, immunohistochemistry, and behavioral assays were used 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 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. CONCLUSIONS: Our results suggest that IQSEC3-mediated balanced synaptic inhibition in hippocampal CA1 is critical for the proper formation of hippocampus-dependent fear memory.