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 inhibition 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.

中文翻译：

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IQSEC3 缺失通过上调海马核糖体 S6K1 信号传导损害恐惧记忆

背景

IQSEC3 是一种结合 gephyrin 的 GABA 能（γ-氨基丁酸能）突触特异性鸟嘌呤核苷酸交换因子，最近据报道它可以调节活性依赖性 GABA 能突触成熟，但其潜在的信号传导机制仍未完全了解。

方法

我们生成了条件性敲除 Iqsec3 (cKO) 的小鼠，以检查改变的突触抑制是否影响海马依赖性恐惧记忆的形成。此外，电生理记录、免疫组织化学和行为分析被用来解决我们的问题。

结果

我们发现Iqsec3 -cKO 诱导 GABAergic 突触密度、GABAergic 突触传递和海马 CA1 区域长期增强的维持特异性降低。此外，Iqsec3 -cKO 小鼠表现出恐惧记忆形成受损。引人注目的是，Iqsec3 -cKO 导致海马体中核糖体 P70-S6K1 介导的信号激活异常增强，但皮质中没有。此外，通过在Iqsec3的海马 CA1 中表达显性阴性 S6K1 来抑制上调的 S6K1 信号-cKO 小鼠完全恢复了受损的恐惧学习和抑制性突触密度，但没有恢复长期增强维持功能。最后，上调的 S6K1 信号被 IQSEC3 野生型拯救，但不是由 ARF-GEF（二磷酸腺苷核糖基化因子 - 鸟嘌呤核苷酸交换因子）失活的 IQSEC3 突变体拯救。

结论

我们的研究结果表明，IQSEC3 介导的海马 CA1 平衡突触抑制对于海马依赖性恐惧记忆的正确形成至关重要。