苏州大学镇学初小组近日取得一项新成果。经过不懈努力，他们探明了抗精神病药物拯救线粒体羟化酶Clk1突变小鼠的选择性识别记忆障碍。相关论文于2025年9月1日发表于国际顶尖学术期刊《中国药理学报》杂志上。

鉴于学习和记忆在药物依赖中的关键作用，课题组在此探讨Clk1缺乏是否以及如何影响小鼠的认知过程。研究组发现突变的Clk1小鼠（Clk1^+/-）在新物体识别（NOR）和新手臂识别（NAR）测试中表现出识别记忆障碍。此外，研究组观察到Clk^+/-突变小鼠的前额叶皮层（PFC）的树突棘密度选择性减少，而海马区（HIP）的树突棘密度没有选择性减少。脑源性神经营养因子（BDNF）的表达在PFC中降低，而在HIP中没有。

此外,Clk1^+/-突变小鼠在PFC的ERK/CREB信号通路中表现出损伤，这可能是Clk1^+/-突变诱导的BDNF和树突形态的变化。连续7天服用抗精神病药物阿立哌唑（0.3 mg·kg^-1·d^-1,i.p.)或利培酮（1mg·kg^-1·d^-1,i.p.)完全恢复了Clk1突变引起的识别记忆缺陷。本研究提供了主要证据，强调了线粒体Clk1在识别记忆调节中的作用，并为研究线粒体在学习和记忆中的功能提供了一个信息模型。

据了解，线粒体不仅是真核细胞中最重要的细胞器，参与能量代谢、信号转导、细胞凋亡等生理过程，也是神经发育、神经可塑性、存活和成体神经发生的重要调节因子。线粒体定位的羟化酶Clk-1参与泛醌的生物合成。最近的证据表明，Clk1^+/-突变小鼠对吗啡和甲基苯丙胺诱导的条件位置偏好有抵抗力。

附：英文原文

Title: Selective recognition memory impairment in mitochondrial hydroxylase Clk1 mutant mice, rescued by antipsychotics

Author: Shi, Zhi-feng, Yu, Zhe-xiang, Gu, Ling-han, Ma, Zhi-xue, Chen, Qin-bo, Wen, Li-bin, Waddington, John L., Zhen, Xue-chu

Issue&Volume: 2025-09-01

Abstract: Mitochondria are not only the most important organelles in eukaryotic cells that participate in energy metabolism, signal transduction, cell apoptosis and other physiological processes, but also essential regulators of neurodevelopment, neuroplasticity, survival and adult neurogenesis. The mitochondria-localized hydroxylase Clk-1 is involved in ubiquinone biosynthesis. Recent evidence shows that Clk1+/ mutant mice are resistant to morphine- and methamphetamine-induced conditioned place preference. Given the critical role of learning and memory in drug dependence, we herein explored whether and how Clk1 deficiency affected the cognitive processes in mice. We found that mutant Clk1 mice (Clk1+/) exhibited recognition memory impairment in novel object recognition (NOR) and novel arm recognition (NAR) tests. In addition, we observed in Clk1+/ mutant mice a selective reduction in dendritic spine density in prefrontal cortex (PFC) but not in the hippocampus (HIP). The expression of brain-derived neurotrophic factor (BDNF) was also decreased in PFC but not in HIP. Furthermore, Clk1+/ mutant mice displayed impairment in the ERK/CREB signaling pathway in PFC that might underlie Clk1+/ mutation-induced changes in BDNF and dendritic morphology. Administration of antipsychotic drugs aripiprazole (0.3mg·kg1·d1, i.p.) or risperidone (1mg·kg1·d1, i.p.) for 7 days fully rescued Clk1 mutation-induced recognition memory deficits. This study provides primary evidence highlighting the role of mitochondrial Clk1 in the regulation of recognition memory and presents an informative model for investigating mitochondrial function in learning and memory.

DOI: 10.1038/s41401-025-01641-4

Source: https://www.nature.com/articles/s41401-025-01641-4