Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.
Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.
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DOI：
10.3389/fnbeh.2016.00136
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发表时间：
2016
影响因子：
3
通讯作者：
McBride SM
中科院分区：
文献类型：
--
作者：
Choi CH;Schoenfeld BP;Bell AJ;Hinchey J;Rosenfelt C;Gertner MJ;Campbell SR;Emerson D;Hinchey P;Kollaros M;Ferrick NJ;Chambers DB;Langer S;Sust S;Malik A;Terlizzi AM;Liebelt DA;Ferreiro D;Sharma A;Koenigsberg E;Choi RJ;Louneva N;Arnold SE;Featherstone RE;Siegel SJ;Zukin RS;McDonald TV;Bolduc FV;Jongens TA;McBride SM
脆性X染色体是最常见的与智力残疾（ID）和自闭症谱系障碍（ASD）相关的单基因疾病。此外，许多患者患有执行功能障碍、ADHD、癫痫发作障碍和睡眠障碍。脆性X是由FMR 1基因编码的FMRP表达缺失引起的。脆性X的果蝇和小鼠模型也是基于它们各自的FMR 1同源物没有功能性蛋白表达。苍蝇模型显示出明确的认知障碍和结构性脑缺陷，而小鼠模型虽然具有细微的行为缺陷，但具有稳健的电生理表型，并提供了对选择的脑区域进行广泛生物化学分析的工具。在来自脆性X染色体的苍蝇和小鼠模型的样品以及来自人类患者的样品中观察到cAMP信号传导减少。事实上，我们先前已经证明，增加cAMP信号传导的策略可以挽救果蝇模型中的短期记忆，并在小鼠模型中将海马中DHPG诱导的mGluR介导的长期抑制（LTD）恢复到适当水平（McBride等人，; Choi等人，）。在这里，我们证明了之前使用的具有临床应用潜力的相同三种策略，锂治疗，PDE-4抑制剂治疗或mGluR拮抗剂治疗可以挽救果蝇模型中的长期记忆并改变小鼠模型海马中的cAMP信号通路。
Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al.,; Choi et al.,). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.