Guangdong Provincial Key Laboratory of Functional Proteomics, Key Laboratory of Mental Health of the Ministry of Education, School of Basic Medical Sciences, Pediatric Center of Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Histology and Embryology, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Key Laboratory of Construction and Detection in Tissue Engineering of Guangdong Province, School of Basic Medical Sciences, Center for Orthopaedic Surgery of the Third Affiliated Hospital, Southern Medical University, Guangzhou 510515, China.
Guangdong Provincial Key Laboratory of Functional Proteomics, Key Laboratory of Mental Health of the Ministry of Education, School of Basic Medical Sciences, Pediatric Center of Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166569. doi: 10.1016/j.bbadis.2022.166569. Epub 2022 Oct 13.
Hippocampus plays critical roles in drug addiction. Cocaine-induced modifications in dopamine receptor function and the downstream signaling are important regulation mechanisms in cocaine addiction. Rac regulates actin filament accumulation while Cdc42 stimulates the formation of filopodia and neurite outgrowth. Based on the region specific roles of small GTPases in brain, we focused on the hippocampal subregions to detect the regulation of Cdc42 signaling in long-term morphological and behavioral adaptations to cocaine.
Genetically modified mouse models of Cdc42, dopamine receptor D1 (D1R) and D2 (D2R) and expressed Cdc42 point mutants that are defective in binding to and activation of its downstream effector molecules PAK and N-WASP were generated, respectively, in CA1 or dentate gyrus (DG) subregion.
Cocaine induced upregulation of Cdc42 signaling activity. Cdc42 knockout or mutants blocked cocaine-induced increase in spine plasticity in hippocampal CA1 pyramidal neurons, leading to a decreased conditional place preference (CPP)-associated memories and spatial learning and memory in water maze. Cdc42 knockout or mutants promoted cocaine-induced loss of neurogenesis in DG, leading to a decreased CPP-associated memories and spatial learning and memory in water maze. Furthermore, by using D1R knockout, D2R knockout, and D2R/Cdc42 double knockout mice, we found that D2R, but not D1R, regulated Cdc42 signaling in cocaine-induced neural plasticity and behavioral changes.
Cdc42 acts downstream of D2R in the hippocampus and plays an important role in cocaine-induced neural plasticity through N-WASP and PAK-LIMK-Cofilin, and Cdc42 signaling pathway correlatively links specific brain regions (CA1, dentate gyrus) to cocaine-induced CPP behavior.
海马体在药物成瘾中起着关键作用。可卡因诱导的多巴胺受体功能改变及其下游信号转导是可卡因成瘾的重要调节机制。Rac 调节肌动蛋白丝的积累，而 Cdc42 刺激丝状伪足和神经突生长的形成。基于小 GTPases 在大脑中的区域特异性作用，我们专注于海马亚区，以检测 Cdc42 信号转导在长期形态和行为适应可卡因中的调节作用。
分别在 CA1 或齿状回（DG）亚区中生成 Cdc42、多巴胺受体 D1（D1R）和 D2（D2R）的基因修饰小鼠模型，以及表达不能与下游效应分子 PAK 和 N-WASP 结合和激活的 Cdc42 点突变体。
可卡因诱导 Cdc42 信号转导活性的上调。Cdc42 敲除或突变体阻断了可卡因诱导的海马 CA1 锥体神经元中棘突可塑性的增加，导致条件位置偏好（CPP）相关记忆和水迷宫中的空间学习和记忆减少。Cdc42 敲除或突变体促进了 DG 中可卡因诱导的神经发生丢失，导致 CPP 相关记忆和水迷宫中的空间学习和记忆减少。此外，通过使用 D1R 敲除、D2R 敲除和 D2R/Cdc42 双敲除小鼠，我们发现 D2R 而不是 D1R 调节了可卡因诱导的神经可塑性和行为变化中的 Cdc42 信号转导。
Cdc42 在海马体中作为 D2R 的下游分子发挥作用，通过 N-WASP 和 PAK-LIMK-Cofilin 参与可卡因诱导的神经可塑性，并通过 Cdc42 信号通路将特定脑区（CA1、齿状回）与可卡因诱导的 CPP 行为相关联。
