Bolla Maria, Colombo Giulia, Falappa Matteo, Pace Marta, Baravalle Roman, Martinez Nataniel, Montani Fernando, Tucci Valter, Cancedda Laura
Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, Via Morego, 30, 16163 Genoa, Italy.
Università Degli Studi di Genova, Via Balbi, 5, 16126 Genoa, Italy.
iScience. 2025 Mar 13;28(4):112220. doi: 10.1016/j.isci.2025.112220. eCollection 2025 Apr 18.
In several brain disorders, the hyperpolarizing/inhibitory effects of GABA signaling through Cl-permeable GABA receptors are compromised, leading to an imbalance between neuronal excitation and inhibition. For example, the Ts65Dn mouse model of Down syndrome (DS) exhibits increased expression of the Cl importer NKCC1, leading to depolarizing gamma aminobutyric acid (GABA) signaling in the mature hippocampus and cortex. Inhibiting NKCC1 with the Food and Drug Administration (FDA)-approved diuretic bumetanide rescues inhibitory GABAergic transmission, synaptic plasticity, and cognitive functions in adult Ts65Dn mice. Given that DS individuals and Ts65Dn mice show sleep disturbances, and considering the key role of GABAergic transmission in sleep, we investigated whether NKCC1 upregulation contributes to sleep abnormalities in adult Ts65Dn mice. Chronic oral administration of bumetanide ameliorated the spectral profile of sleep, sleep architecture, and electroencephalogram (EEG) entropy/complexity, accompanied by a lower hyperactivity in trisomic mice. These results offer a potential avenue for addressing common sleep disturbances in DS.
在几种脑部疾病中，通过氯离子通透型γ-氨基丁酸（GABA）受体介导的GABA信号的超极化/抑制作用受损，导致神经元兴奋与抑制之间失衡。例如，唐氏综合征（DS）的Ts65Dn小鼠模型显示氯离子导入体NKCC1表达增加，导致成熟海马体和皮质中γ-氨基丁酸（GABA）信号去极化。用美国食品药品监督管理局（FDA）批准的利尿剂布美他尼抑制NKCC1可挽救成年Ts65Dn小鼠的抑制性GABA能传递、突触可塑性和认知功能。鉴于DS个体和Ts65Dn小鼠存在睡眠障碍，并且考虑到GABA能传递在睡眠中的关键作用，我们研究了NKCC1上调是否导致成年Ts65Dn小鼠出现睡眠异常。长期口服布美他尼改善了睡眠的频谱特征、睡眠结构和脑电图（EEG）熵/复杂度，同时三体小鼠的多动性降低。这些结果为解决DS常见的睡眠障碍提供了一条潜在途径。
