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

作者：Yang Yang, Xiaoxuan Sun, Yaoyao Sun, Yaoyao Sun, Xiaoyang Feng, Liwei Mei, Xiaqin Sun, 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 · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adv4779 · 被引用次数：2 · 研究领域：Tryptophan and brain disorders、Neuroscience and Neuropharmacology Research、Adipose Tissue and Metabolism

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.