Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
Department of Biology, University of Houston, Houston, TX, USA.
Mol Neurobiol. 2018 Jul;55(7):5951-5961. doi: 10.1007/s12035-017-0819-5. Epub 2017 Nov 11.
Fragile X Syndrome (FXS) is the leading cause of autism spectrum disorder and intellectual disability and results from loss of Fragile X mental retardation protein (FMRP). In neurons, FMRP controls the translation of synaptic plasticity proteins that are implicated in learning and memory. FMRP also regulates development- and experience-dependent actin cytoskeleton remodeling within dendritic spines through the small Rho GTPase Rac1. Modulation of Rac1 activity is critical during synaptic plasticity as well as learning and memory. We have previously shown that FXS mouse models exhibit learning and memory deficits as well as hyperactive Rac1 in the hippocampus. To determine whether pharmacological inhibition of Rac1 in FXS improves cognitive impairment, FXS mice were treated with the specific Rac1 inhibitor NSC23766, followed by fear conditioning. Whereas non-cognitive functions were unaffected, hippocampus-related memory improved in FXS mice treated with the Rac1 inhibitor. Furthermore, long-term potentiation in hippocampal slices from FXS mice was increased after incubation with the Rac1 inhibitor. Together, these observations indicate that modulation of Rac1 may provide a novel therapeutic target in the treatment of cognitive impairment in FXS.
脆性 X 综合征（FXS）是自闭症谱系障碍和智力残疾的主要原因，其病因是脆性 X 智力低下蛋白（FMRP）缺失。在神经元中，FMRP 控制着突触可塑性蛋白的翻译，这些蛋白与学习和记忆有关。FMRP 还通过小 Rho GTPase Rac1 调节树突棘内发育和经验依赖性肌动蛋白细胞骨架重塑。Rac1 活性的调节在突触可塑性以及学习和记忆中至关重要。我们之前的研究表明，FXS 小鼠模型表现出学习和记忆缺陷以及海马中 Rac1 的过度活跃。为了确定 FXS 中 Rac1 的药理学抑制是否改善认知障碍，用特异性 Rac1 抑制剂 NSC23766 处理 FXS 小鼠，然后进行恐惧条件反射。虽然非认知功能不受影响，但 Rac1 抑制剂处理的 FXS 小鼠的海马相关记忆得到改善。此外，用 Rac1 抑制剂孵育后，FXS 小鼠海马切片中的长时程增强增加。综上所述，这些观察结果表明，Rac1 的调节可能为 FXS 认知障碍的治疗提供新的治疗靶点。
