Anxiety disorders are the most common psychiatric disorders, and the change in the activity of the prefrontal cortex (PFC) is considered as the underlying pathological mechanism. Parvalbumin-expressing (PV+) inhibition contributes to the overall activity of the PFC. However, the molecular mechanism underlying the excitation-inhibition imbalance of PV+ neurons in the PFC is unknown. Efnb2 is a membrane-bound molecule that plays an important role in the nervous system through binding the Eph receptor. To investigate whether the loss of Efnb2 in PV+ affects anxiety, we examined the behavior of wild type and Efnb2 in PV+ neurons knockout (KO) mice. We monitored the defensive responses to aversive stimuli of elevated plus maze (EPM) and found that KO mice exhibited obvious fearless and anxiolytic behaviors. To further investigate the underlying regulatory mechanism, we performed RNA sequencing, analyzed the differentially expressed genes (DEGs), and constructed the weighted gene co-expression network analysis (WGCNA). The WGCNA identified 12 characteristic modules. Among them, the MEgreen module showed the most significant correlation with KO mice of EPM stimuli. The Gene Ontology enrichment and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that this was related to the distal axon, Ras signaling pathway and insulin signaling pathway. Furthermore, the whole-cell voltage clamp recordings also proved that Efnb2 gene knock-out could affect synaptic function. Together with the transcriptomic analysis of mice with Efnb2 knockout on PV+ neurons, our findings suggest that Efnb2 gene in the PV+ neuron of PFC may be a crucial factor for fear and anxiety, which provide an insight into anxiety pathophysiology.

中文翻译：

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RNA-seq 共表达网络分析揭示 Efnb2 敲除小鼠小白蛋白 + 神经元的抗焦虑行为


焦虑症是最常见的精神疾病，前额皮质（PFC）活动的变化被认为是潜在的病理机制。小白蛋白表达 (PV+) 抑制有助于 PFC 的整体活性。然而，PFC 中 PV+ 神经元兴奋抑制失衡的分子机制尚不清楚。 Efnb2 是一种膜结合分子，通过结合 Eph 受体在神经系统中发挥重要作用。为了研究 PV+ 中 Efnb2 的缺失是否会影响焦虑，我们检查了 PV+ 神经元敲除 (KO) 小鼠中野生型和 Efnb2 的行为。我们监测了高架十字迷宫（EPM）厌恶刺激的防御反应，发现KO小鼠表现出明显的无所畏惧和抗焦虑行为。为了进一步研究潜在的调控机制，我们进行了RNA测序，分析了差异表达基因（DEG），并构建了加权基因共表达网络分析（WGCNA）。 WGCNA 确定了 12 个特征模块。其中，MEgreen模块与EPM刺激的KO小鼠表现出最显着的相关性。 Gene Ontology富集和京都基因与基因组百科全书富集分析表明，这与远端轴突、Ras信号通路和胰岛素信号通路有关。此外，全细胞电压钳记录也证明Efnb2基因敲除会影响突触功能。结合对 PV+ 神经元 Efnb2 敲除小鼠的转录组分析，我们的研究结果表明 PFC PV+ 神经元中的 Efnb2 基因可能是恐惧和焦虑的关键因素，这为了解焦虑的病理生理学提供了见解。