Pittaras Elsa C, Artal Jonathan M, Ajibola Grace, Allocca Giancarlo, Bennett Mia, Camargo Alexandra, Carpio Angelica, Gessner Nicholas, Hinton Myles, Pizzitola Rebecca, Tan Natalie, Zhang Evelyn, Zhong Alan, Heller Horace C
Department of Biology, Stanford University, Stanford, CA, USA.
Stanford Law School, Stanford University, Stanford, CA, USA.
Sleep. 2025 May 12;48(5). doi: 10.1093/sleep/zsae300.
Down syndrome (DS) is a common genetic condition affecting people worldwide. It involves cognitive disabilities for which there are no drug therapies. The Ts65Dn mouse model of DS shows cognitive impairment due to a reduction in neuron number and connectivity as well as excessive neuronal activity, as γ-aminobutyric acid (GABA) antagonist treatment restores memory in these mice. Our study showed the effects of GABA antagonist treatment on sleep and decision-making in Ts65Dn mice. We administered a daily, low oral dose of pentylenetetrazol (PTZ) in milk to Ts65Dn mice for 17 days. Decision-making was tested with and without PTZ treatment. Short and long-term memories were tested before, immediately after, and 1 month following PTZ treatment. Electro-encephalography was also recorded at these three time points to study the effect of the treatment on sleep. We showed that PTZ treatment improved long-term recognition, but not short term memory and led to more Ts65Dn mice showing safer decision-making behavior. PTZ treatment showed a moderate and only global beneficial effect on sleep by decreasing the global amount of wake and increasing non-rapid eye movement sleep in the Ts65Dn mice, which may explain the observed cognitive improvements. These results bring new knowledge on the role of GABA in sleep, memory consolidation, and decision-making abilities in DS.
唐氏综合征（DS）是一种影响全球人群的常见遗传疾病。它会导致认知障碍，目前尚无药物治疗方法。DS的Ts65Dn小鼠模型显示出认知障碍，原因是神经元数量和连接减少以及神经元活动过度，因为γ-氨基丁酸（GABA）拮抗剂治疗可恢复这些小鼠的记忆。我们的研究显示了GABA拮抗剂治疗对Ts65Dn小鼠睡眠和决策的影响。我们每天给Ts65Dn小鼠经口灌胃低剂量的戊四氮（PTZ），持续17天。在有和没有PTZ治疗的情况下测试决策能力。在PTZ治疗前、治疗后立即以及治疗后1个月测试短期和长期记忆。还在这三个时间点记录脑电图，以研究治疗对睡眠的影响。我们发现PTZ治疗改善了长期识别能力，但未改善短期记忆，并使更多的Ts65Dn小鼠表现出更安全的决策行为。PTZ治疗通过减少Ts65Dn小鼠的总觉醒量并增加非快速眼动睡眠，对睡眠产生了适度且仅为整体的有益影响，这可能解释了观察到的认知改善。这些结果为GABA在DS的睡眠、记忆巩固和决策能力中的作用带来了新知识。
