Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior
Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior
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DOI：
10.1016/j.celrep.2021.109417
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发表时间：
2021-07-21
期刊：
影响因子：
8.8
通讯作者：
Ko, Jaewon
中科院分区：
文献类型：
--
作者：
Kim, Seungjoon;Park, Dongseok;Ko, Jaewon
活动依赖性gaba能突触可塑性对正常脑功能很重要，但其潜在的分子机制尚未完全了解。在这里，我们发现Npas4（神经元pas结构域蛋白4）通过转录调控IQSEC3的表达，IQSEC3是一种gaba能突触特异性鸟嘌呤核苷酸交换因子，用于adp核糖基化因子（ARF-GEF），直接与gephyrin相互作用。富集环境激活神经元可诱导npas4介导的IQSEC3蛋白的上调，特别是在CA1层生长抑素（SST）表达gaba能的中间神经元中。Npas4的SST+中间神经元特异性敲除（KO）破坏了这些gaba能中间神经元的突触传递，增加了CA1锥体神经元的神经元活性，并减少了焦虑行为，所有这些都是通过野生型IQSEC3的表达正常化的，而不是在Npas4-KO小鼠的SST+中间神经元中表达显性阴性的arf - gef失活突变体。我们的研究结果表明，IQSEC3是一个关键的gaba能突触成分，由Npas4和ARF活性指导，特别是在SST+中间神经元中，协调兴奋-抑制平衡和控制焦虑样行为。
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.