α1-Na/K-ATPase inhibition rescues aberrant dendritic calcium dynamics and memory deficits in the hippocampus of an Angelman syndrome mouse model.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of the maternal copy of the UBE3A gene. Previous studies reported an increase in α1-Na/K-ATPase (α1-NaKA) expression in the AS hippocampus at the age of 2 weeks as the initial and isolated molecular alteration. This increase was further implied upon actuating much of the hippocampal-related deficits in an AS mouse model, although the underlying mechanism was never investigated. Here, we showed that enhanced α1-NaKA expression resulted in increased pump activity that reduced activity-dependent dendritic Ca2+ dynamics in the AS hippocampus, as well as selective inhibition of α1-NaKA by marinobufagenin (MBG) to normalize these aberrant Ca2+ dynamics. In addition, we demonstrated that selective α1-NaKA inhibition corrected impaired hippocampal synaptic plasticity and hippocampal-dependent cognitive deficits. Furthermore, we showed that the isolated increase in hippocampal α1-NaKA expression in AS mice at 2 weeks of age was accompanied by an unexpected enhancement in excitability. Altogether, our study implicates the modification of Ca2+ dynamics as one of the major underlying mechanisms by which enhanced α1-NaKA expression induces deleterious effects in the hippocampus of AS model mice. Finally, we propose a therapeutic approach for AS and possibly other neurodevelopmental disorders that entail aberrant NaKA expression or abnormal Ca2+ dynamics.