Nkapl deletion drives cognitive deficits through mPFC interneuron dysfunction in a mouse model of schizophrenia

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-10-01 DOI:10.1126/sciadv.adv4779

Yang Yang, Xiaoxuan Sun, Yaoyao Sun, Xiaoyang Feng, Liwei Mei, Xiaqin Sun, Zhe Lu, Yuyanan Zhang, Liangkun Guo, Guorui Zhao, Zhewei Kang, Junyuan Sun, Jing Guo, Yundan Liao, Yunqing Zhu, Rui Yuan, Tianlan Lu, Jun Li, Dai Zhang, Kai Gao, Weihua Yue

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Abstract

Cognitive dysfunction is a core feature of schizophrenia (SCZ), yet its mechanisms remain poorly understood. We investigated the functional role of NKAPL (nuclear factor κB activating protein-like)—an SCZ risk-associated gene—and the single nucleotide polymorphism rs1635 in cognitive deficits related to SCZ. We used Nkapl transgenic mouse models to explore the impact of NKAPL on SCZ-related cognitive deficits. NKAPL acts as a transcriptional repressor of the γ-aminobutyric acid (GABA) metabolizing enzyme succinic semialdehyde dehydrogenase (SSADH). Nkapl deletion in medial prefrontal cortex (mPFC) interneurons led to increased SSADH levels, reduced GABA concentration in the synaptic cleft, impaired inhibitory synaptic transmission, and cognitive deficits. Furthermore, the rs1635 mutation (T153N) caused similar effects as the Nkapl knockout. Reexpression of wild-type NKAPL or genetic knockdown of SSADH in mPFC interneurons restored the synaptic dysfunction and cognitive deficits in Nkapl^−/− mice. Our study indicates the potential role of NKAPL and SSADH in mPFC interneurons in neuronal mechanisms of learning and memory in mice.

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在精神分裂症小鼠模型中，Nkapl缺失通过mPFC中间神经元功能障碍驱动认知缺陷

认知功能障碍是精神分裂症（SCZ）的核心特征，但其机制尚不清楚。我们研究了SCZ风险相关基因NKAPL（核因子κB激活蛋白样）和单核苷酸多态性rs1635在SCZ相关认知缺陷中的功能作用。我们利用Nkapl转基因小鼠模型探讨Nkapl对scz相关认知缺陷的影响。NKAPL作为γ-氨基丁酸（GABA）代谢酶琥珀酸半醛脱氢酶（SSADH）的转录抑制因子。内侧前额叶皮层（mPFC）中间神经元的Nkapl缺失导致SSADH水平升高，突触间隙中GABA浓度降低，抑制性突触传递受损和认知缺陷。此外，rs1635突变（T153N）引起的影响与Nkapl敲除相似。野生型NKAPL的重表达或mPFC中间神经元中SSADH的基因敲低可恢复NKAPL−/−小鼠的突触功能障碍和认知缺陷。本研究揭示了mPFC中间神经元NKAPL和SSADH在小鼠学习记忆神经元机制中的潜在作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.