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

Abstract

In several brain disorders, the hyperpolarizing/inhibitory effects of GABA signaling through Cl-permeable GABAA 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 hippocampusand cortex. Inhibiting NKCC1 with the Food and Drug Administration (FDA)-approved diuretic bumetaniderescues inhibitory GABAergic transmission, synaptic plasticity, and cognitive functions in adultTs65Dn mice.Given that DS individuals and Ts65Dn mice show sleep disturbances, and considering the key role ofGABAergic transmission in sleep, we investigated whether NKCC1 upregulation contributes to sleep abnormalitiesin adult Ts65Dn mice. Chronic oral administration of bumetanide ameliorated the spectral profile ofsleep, sleep architecture, and electroencephalogram (EEG) entropy/complexity, accompanied by a lower hyperactivityin trisomic mice. These results offer a potential avenue for addressing common sleep disturbancesin DS.