Hanoch Kaphzan,Shelly A. Buffington,Akila B. Ramaraj,Jerry B. Lingrel,Matthew N. Rasband,Emanuela Santini and Eric Klann
SUMMARY
Angelman syndrome (AS) is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (a1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in a1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that a1-NaKA overexpression drives AIS abnormalities and that by reducing its expression these and other phenotypes could be corrected in AS model mice. Herein, we report that the genetic normalization of a1-NaKA levels in AS model mice corrects multiple hippocampal phenotypes, including alterations in the AIS, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. These findings strongly suggest that increased expression of a1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice.
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