Hovav Hadas Catane, Kashi Ofer Yitzhak, Abu Ghanem Yumna, Stochinsky Naomi, Agbariya Laila, Yehuda Hila, Weitz-Aviv Moriya, Baraghithy Saja, Tam Joseph, Yaka Rami, Umschweif Gali
Laboratory of Cellular and Molecular Psychiatry, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Laboratory of Neurobiology of Drug Addiction, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Transl Psychiatry. 2025 Jul 2;15(1):225. doi: 10.1038/s41398-025-03448-7.
Major depressive disorder (MDD) affects millions worldwide, yet its pathophysiology remains poorly understood. While some individuals are susceptible to developing depression, others show resilience that protects them from developing MDD. Understanding the resilience-associated mechanisms will likely result in novel therapies for MDD. We have recently reported that the vesicular protein Neurensin-2 mediates depression and that its deletion confers profound resilience to chronic stress. Nonetheless, the behavioral and molecular adaptations that underlie the stress resilience in Neurensin-2 knockout mice are still unknown. In this study, we aimed to comprehensively characterize the basal behavioral effects of Neurensin-2 deletion in mice. We used Neurensin-2 knockout male and female mice to examine how Neurensin-2 deletion affects cognitive, emotional, and motor performance in mice. In addition, we examined the impact of Neurensin-2 deletion on body weight, analyzed the stress-induced molecular changes, and tested how these changes affect the excitatory/inhibitory balance. We found that while Neurensin-2 deletion confers basal anxiolysis and weight reduction, no discernible cognitive, social, or motor impairments were detected. Furthermore, we found that Neurensin-2 knockout mice have impaired hippocampal inhibitory transmission, which is resilient to the stress-evoked excitatory/inhibitory imbalance seen in wild-type mice. Our findings suggest that Neurensin-2 deletion confers basal anxiolysis, and shifts the hippocampal excitatory/inhibitory balance. These effects are not accompanied by impaired cognitive function or weight gain. Thus, we suggest Neurensin-2 inhibition as an exciting potential strategy for developing treatments for depression and anxiety disorders as well as for promoting stress resilience.
重度抑郁症（MDD）影响着全球数百万人，但其病理生理学仍知之甚少。虽然有些人易患抑郁症，但另一些人则表现出抵御能力，使他们免受MDD的困扰。了解与抵御能力相关的机制可能会带来治疗MDD的新疗法。我们最近报告称，囊泡蛋白神经ensin-2介导抑郁症，其缺失赋予对慢性应激的强大抵御能力。尽管如此，神经ensin-2基因敲除小鼠应激抵御能力背后的行为和分子适应性仍不清楚。在本研究中，我们旨在全面表征小鼠中神经ensin-2缺失的基础行为效应。我们使用神经ensin-2基因敲除的雄性和雌性小鼠来研究神经ensin-2缺失如何影响小鼠的认知、情绪和运动表现。此外，我们研究了神经ensin-2缺失对体重的影响，分析了应激诱导的分子变化，并测试了这些变化如何影响兴奋性/抑制性平衡。我们发现，虽然神经ensin-2缺失可导致基础抗焦虑和体重减轻，但未检测到明显的认知、社交或运动障碍。此外，我们发现神经ensin-2基因敲除小鼠的海马抑制性传递受损，而这种抑制性传递对野生型小鼠中应激诱发的兴奋性/抑制性失衡具有抵御能力。我们的研究结果表明，神经ensin-2缺失可导致基础抗焦虑，并改变海马兴奋性/抑制性平衡。这些效应并未伴随着认知功能受损或体重增加。因此，我们建议抑制神经ensin-2作为一种令人兴奋的潜在策略，用于开发治疗抑郁症和焦虑症的方法以及促进应激抵御能力。
