NKCC1 inhibition improves sleep quality and EEG information content in a Down syndrome mouse model

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-03-13 DOI:10.1016/j.isci.2025.112220

Maria Bolla , Giulia Colombo , Matteo Falappa , Marta Pace , Roman Baravalle , Nataniel Martinez , Fernando Montani , Valter Tucci , Laura Cancedda

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Abstract

In several brain disorders, the hyperpolarizing/inhibitory effects of GABA signaling through Cl-permeable GABA_A 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.

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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