Long-lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5-selective GABAA inverse agonist
Long-lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5-selective GABAA inverse agonist
复制标题
DOI：
10.1111/bph.14903
复制
发表时间：
2020-03-01
影响因子：
7.3
通讯作者：
Potier, Marie-Claude
中科院分区：
文献类型：
--
作者：
Duchon, Arnaud;Gruart, Agnes;Potier, Marie-Claude
背景与目的过度的GABA能抑制导致唐氏综合征(DS)患者的认知功能障碍。含有α5的GABA(A)受体的选择性负变构调节剂(NAM)，如α5反向激动剂(α5IA)，可恢复DS模型Ts65Dn小鼠的学习和记忆障碍。在这项研究中，我们评估了阿尔法5IA对Ts65Dn小鼠体内LTP和行为的长期影响。实验方法我们在自由活动的Ts65Dn小鼠及其野生型窝种上进行了连续6天的体内LTP记录，用赋形剂或阿尔法5IA处理。同时，对Ts65Dn小鼠进行不同的学习和记忆测试(Y迷宫、Morris水迷宫或新物体识别)，持续7d。然而，在单次注射阿尔法5IA后，这种缺陷至少在连续六天内得到了可持续的逆转。在评估Ts65Dn小鼠的工作和长期记忆缺陷时，也观察到了阿尔法5IA的这种长期效应。结论和启示我们首次在体内显示了Ts65Dn小鼠的LTP缺陷。这些缺陷在阿尔法5IA急性治疗后至少恢复了6天，可能是阿尔法5IA对空间工作和长期识别和空间记忆任务的长期药理作用的底物。我们的结果表明，含有α5的GABA(A)受体的负变构调节剂与治疗与DS相关的认知障碍有关。
Background and Purpose Excessive GABAergic inhibition contributes to cognitive dysfunctions in Down syndrome (DS). Selective negative allosteric modulators (NAMs) of alpha 5-containing GABA(A) receptors such as the alpha 5 inverse agonist (alpha 5IA) restore learning and memory deficits in Ts65Dn mice, a model of DS. In this study we have assessed the long-lasting effects of alpha 5IA on in vivo LTP and behaviour in Ts65Dn mice.Experimental Approach We made in vivo LTP recordings for six consecutive days in freely moving Ts65Dn mice and their wild-type littermates, treated with vehicle or alpha 5IA. In parallel, Ts65Dn mice were assessed by various learning and memory tests (Y maze, Morris water maze, or the novel object recognition) for up to 7 days, following one single injection of alpha 5IA or vehicle.Key Results LTP was not evoked in vivo in Ts65Dn mice at hippocampal CA3-CA1 synapses. However, this deficit was sustainably reversed for at least six consecutive days following a single injection of alpha 5IA. This long-lasting effect of alpha 5IA was also observed when assessing working and long-term memory deficits in Ts65Dn mice.Conclusion and Implications We show for the first time in vivo LTP deficits in Ts65Dn mice. These deficits were restored for at least 6 days following acute treatment with alpha 5IA and might be the substrate for the long-lasting pharmacological effects of alpha 5IA on spatial working and long-term recognition and spatial memory tasks. Our results demonstrate the relevance of negative allosteric modulators of alpha 5-containing GABA(A) receptors to the treatment of cognitive deficits associated with DS.