title: Genetic reduction of the α1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.
abstract: 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 (α1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in α1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that α1-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 α1-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 α1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice.
authors.affiliation: Center for Neural Science, New York University, New York, NY 10003, USA.
authors.forename: Hanoch
authors.initials: H
authors.lastname: Kaphzan
authors.forename: Shelly A
authors.initials: SA
authors.lastname: Buffington
authors.forename: Akila B
authors.initials: AB
authors.lastname: Ramaraj
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Rasband
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D017204:Angelman Syndrome / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017487:Ankyrins / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000096:biosynthesis; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D062557:NAV1.6 Voltage-Gated Sodium Channel; D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase
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