Discipline of Neuroscience, Department of Neurology and Neurosurgery, Federal University of São Paulo, Paulista Medical School, São Paulo, SP, Brazil.
Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, Mail Stop RBC 6090, Cleveland, OH, 44106-6090, USA.
Sci Rep. 2021 May 4;11(1):9521. doi: 10.1038/s41598-021-89011-y.
Mounting evidence implicates dysfunctional GABAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS). The specific origin and nature of such dysfunction is still under investigation, which is an issue with practical consequences to preclinical and clinical research, as well as to the care of individuals with DS and anxiety disorder or those experiencing seizures in emergency room settings. Here, we investigated the effects of GABAR positive allosteric modulation (PAM) by diazepam on brain activity, synaptic plasticity, and behavior in Ts65Dn mice. We found Ts65Dn mice to be less sensitive to diazepam, as assessed by electroencephalography, long-term potentiation, and elevated plus-maze. Still, diazepam pre-treatment displayed typical effectiveness in reducing susceptibility and severity to picrotoxin-induced seizures in Ts65Dn mice. These findings fill an important gap in the understanding of GABAergic function in a key model of DS.
越来越多的证据表明，GABAR 介导的神经递质传递功能障碍是唐氏综合征（DS）模型小鼠学习和记忆缺陷的潜在原因之一。这种功能障碍的具体起源和性质仍在研究中，这对临床前和临床研究以及对 DS 患者、焦虑症患者或急诊室癫痫发作患者的护理都有实际影响。在这里，我们研究了苯二氮䓬通过正变构调节（PAM）对 Ts65Dn 小鼠大脑活动、突触可塑性和行为的影响。我们发现，与电生理学、长时程增强和高架十字迷宫评估相比，Ts65Dn 小鼠对苯二氮䓬的敏感性降低。然而，苯二氮䓬预处理在降低 Ts65Dn 小鼠皮可替林诱导的癫痫易感性和严重程度方面表现出典型的有效性。这些发现填补了理解 DS 关键模型中 GABA 能功能的重要空白。
