Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Island Medical Program, Department of Cellular and Physiological Sciences, University of British Columbia, Victoria, BC, Canada.
Neurobiol Dis. 2018 May;113:11-22. doi: 10.1016/j.nbd.2018.01.014. Epub 2018 Jan 31.
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood. Previously we have shown that FXS results in learning impairments that involve deficits in N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity in the hippocampal dentate gyrus (DG). Here we tested whether chronic treatment with minocycline can improve these deficits by enhancing NMDA receptor-dependent functional and structural plasticity in the DG. Minocycline treatment resulted in a significant enhancement in NMDA receptor function in the dentate granule cells. This was accompanied by an increase in PSD-95 and GluN2A and GluN2B subunits in hippocampal synaptoneurosome fractions. Minocycline treatment also enhanced dentate granule cell dendritic length and branching. In addition, our results show that chronic minocycline treatment can rescue performance in novel object recognition in FXS mice. These findings indicate that minocycline treatment has both structural and functional benefits for hippocampal cells, which may partly contribute to the pro-cognitive effects minocycline appears to have for treating FXS.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍病因，也是已知的导致自闭症谱系障碍的主要单一基因病因。FXS 患者表现出多种行为缺陷，除了情绪障碍外，还包括轻度至重度认知障碍。目前这种疾病没有治愈方法，但是米诺环素作为 FXS 患者的治疗方法越来越普遍。米诺环素已被报道可以减轻社交行为缺陷，并改善 FXS 患者的言语功能；然而，其作用机制尚不清楚。我们之前已经表明，FXS 导致学习障碍，涉及海马齿状回（DG）中 NMDA 受体依赖性突触可塑性的缺陷。在这里，我们测试了米诺环素的慢性治疗是否可以通过增强 DG 中的 NMDA 受体依赖性功能和结构可塑性来改善这些缺陷。米诺环素治疗导致 DG 中的颗粒细胞中 NMDA 受体功能显著增强。这伴随着海马突触小体部分中 PSD-95 和 GluN2A 和 GluN2B 亚基的增加。米诺环素治疗还增强了颗粒细胞的树突长度和分支。此外，我们的结果表明，慢性米诺环素治疗可以挽救 FXS 小鼠在新物体识别中的表现。这些发现表明，米诺环素治疗对海马细胞具有结构和功能上的益处，这可能部分有助于米诺环素对治疗 FXS 的认知促进作用。
