Genetic reduction of the α1 Subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in angelman syndrome

Hanoch Kaphzan; Shelly A. Buffington; Akila B. Ramaraj; Jerry B. Lingrel; Matthew N. Rasband; Emanuela Santini; Eric Klann

doi:10.1016/j.celrep.2013.07.005

Genetic reduction of the α1 Subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in angelman syndrome

Hanoch Kaphzan, Shelly A. Buffington, Akila B. Ramaraj, Jerry B. Lingrel, Matthew N. Rasband, Emanuela Santini, Eric Klann

Department of Neurobiology

Research output: Contribution to journal › Article › peer-review

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 rangeof abnormalities in the hippocampus of AS model mice

Original language	English
Pages (from-to)	405-412
Number of pages	8
Journal	Cell Reports
Volume	4
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2013.07.005
State	Published - 2013

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants NS034007, NS047384, and NS078718 (E.K.), NS044916 (M.N.R.), and NS073295 (S.A.B.) and by the Angelman Syndrome Foundation (E.K).

Keywords

AXON INITIAL SEGMENT
OBJECT RECOGNITION
MOUSE MODEL
K ATPASE
NA,K-ATPASE
LESIONS
LIGASE
MEMORY
MUTATIONS
INCREASE

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2013.07.005

Cite this

@article{7a0ac337a5f9413b9b5ec79e8fe95d47,

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 rangeof abnormalities in the hippocampus of AS model mice",

keywords = "AXON INITIAL SEGMENT, OBJECT RECOGNITION, MOUSE MODEL, K ATPASE, NA,K-ATPASE, LESIONS, LIGASE, MEMORY, MUTATIONS, INCREASE",

author = "Hanoch Kaphzan and Buffington, {Shelly A.} and Ramaraj, {Akila B.} and Lingrel, {Jerry B.} and Rasband, {Matthew N.} and Emanuela Santini and Eric Klann",

note = "Funding Information: This work was supported by National Institutes of Health grants NS034007, NS047384, and NS078718 (E.K.), NS044916 (M.N.R.), and NS073295 (S.A.B.) and by the Angelman Syndrome Foundation (E.K). ",

year = "2013",

doi = "10.1016/j.celrep.2013.07.005",

language = "English",

volume = "4",

pages = "405--412",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

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T1 - Genetic reduction of the α1 Subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in angelman syndrome

AU - Kaphzan, Hanoch

AU - Buffington, Shelly A.

AU - Ramaraj, Akila B.

AU - Lingrel, Jerry B.

AU - Rasband, Matthew N.

AU - Santini, Emanuela

AU - Klann, Eric

N1 - Funding Information: This work was supported by National Institutes of Health grants NS034007, NS047384, and NS078718 (E.K.), NS044916 (M.N.R.), and NS073295 (S.A.B.) and by the Angelman Syndrome Foundation (E.K).

PY - 2013

Y1 - 2013

N2 - 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 rangeof abnormalities in the hippocampus of AS model mice

AB - 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 rangeof abnormalities in the hippocampus of AS model mice

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KW - K ATPASE

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KW - LESIONS

KW - LIGASE

KW - MEMORY

KW - MUTATIONS

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Genetic reduction of the α1 Subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in angelman syndrome

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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