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在精神分裂症小鼠模型中,Nkapl删除通过mPFC内部神经元功能障碍驱动认知缺陷

Yang Yang^1,2, Xiaoxuan Sun¹, Yaoyao Sun¹

¹Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China.

Science advances

|October 1, 2025

概括

核因子kappa B激活蛋白样 (NKAPL) 基因变异与精神分裂症认知缺陷有关. NKAPL调节大脑中的GABA新陈代谢,其功能障碍会影响学习和记忆.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
分子生物学分子生物学

背景情况:

认知功能障碍是精神分裂症 (SCZ) 的主要症状.
与SCZ相关的认知缺陷背后的精确分子机制尚未完全理解.
NKAPL是一种与SCZ风险相关的基因,但其在认知障碍中的功能作用尚不清楚.

研究的目的:

研究NKAPL和rs1635单核酸多态性在SCZ相关认知缺陷中的作用.
使用转基因小鼠模型探索NKAPL对认知功能的影响.

主要方法:

使用了Nkapl转基因小鼠模型.
研究了NKAPL对半脱酶 (SSADH) 的转录调节.
研究了Nkapl删除在中间前额叶皮层 (mPFC) 内神经元对SSADH水平,GABA度和突触功能的影响.
评估了rs1635突变 (T153N) 对这些参数的影响.
恢复NKAPL表达或击倒SSADH以评估救援效应.

主要成果:

NKAPL作为SSADH的转录抑制剂,是一种代谢GABA的酶.
在mPFC内部神经元中Nkapl的删除增加了SSADH,减少了突触GABA,抑制传播受损,并导致认知缺陷.
rs1635突变模仿了Nkapl淘汰赛的影响.
恢复NKAPL或降低SSADH水平改善了Nkapl淘汰小鼠的突触功能障碍和认知缺陷.

结论:

在mPFC内部神经元中,NKAPL在调节GABA代谢方面发挥着至关重要的作用.
在mPFC内部神经元中NKAPL-SSADH通路的失调有助于SCZ中观察到的认知缺陷.
NKAPL和SSADH是治疗精神分裂症认知障碍的潜在治疗点.

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