Braudeau J, Dauphinot L, Duchon A, Loistron A, Dodd R H, Hérault Y, Delatour B, Potier M C
Centre de Recherche de l'Institut du Cerveau et de Moelle Epinière, INSERM UMRS 975, CNRS UMR7225, UPMC, 75013 Paris, France.
Adv Pharmacol Sci. 2011;2011:153218. doi: 10.1155/2011/153218. Epub 2011 Oct 19.
Decrease of GABAergic transmission has been proposed to improve memory functions. Indeed, inverse agonists selective for α5 GABA-A-benzodiazepine receptors (α5IA) have promnesiant activity. Interestingly, we have recently shown that α5IA can rescue cognitive deficits in Ts65Dn mice, a Down syndrome mouse model with altered GABAergic transmission. Here, we studied the impact of chronic treatment with α5IA on gene expression in the hippocampus of Ts65Dn and control euploid mice after being trained in the Morris water maze task. In euploid mice, chronic treatment with α5IA increased IEGs expression, particularly of c-Fos and Arc genes. In Ts65Dn mice, deficits of IEGs activation were completely rescued after treatment with α5IA. In addition, normalization of Sod1 overexpression in Ts65Dn mice after α5IA treatment was observed. IEG expression regulation after α5IA treatment following behavioral stimulation could be a contributing factor for both the general promnesiant activity of α5IA and its rescuing effect in Ts65Dn mice alongside signaling cascades that are critical for memory consolidation and cognition.
有人提出降低GABA能传递可改善记忆功能。事实上，对α5 GABA-A-苯二氮䓬受体具有选择性的反向激动剂（α5IA）具有促记忆活性。有趣的是，我们最近发现α5IA可以挽救Ts65Dn小鼠的认知缺陷，Ts65Dn小鼠是一种GABA能传递改变的唐氏综合征小鼠模型。在此，我们研究了在Morris水迷宫任务中训练后，α5IA慢性治疗对Ts65Dn小鼠和对照正常小鼠海马体基因表达的影响。在正常小鼠中，α5IA慢性治疗增加了即刻早期基因（IEGs）的表达，尤其是c-Fos和Arc基因。在Ts65Dn小鼠中，用α5IA治疗后IEGs激活缺陷完全得到挽救。此外，观察到α5IA治疗后Ts65Dn小鼠中Sod1过表达的正常化。行为刺激后α5IA治疗后的IEG表达调节可能是α5IA的一般促记忆活性及其对Ts65Dn小鼠的挽救作用的一个促成因素，同时还有对记忆巩固和认知至关重要的信号级联反应。
