APP causes hyperexcitability in fragile X mice

Cara J. Westmark, Shih Chieh Chuang, Seth A. Hays, Mikolaj J. Filon, Brian C. Ray, Pamela R. Westmark, Jay R. Gibson, Kimberly M. Huber, Robert K S Wong

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

Original languageEnglish (US)
Article number147
JournalFrontiers in Molecular Neuroscience
Volume9
Issue numberDEC2016
DOIs
StatePublished - Dec 15 2016

Fingerprint

Amyloid beta-Protein Precursor
Fragile X Syndrome
Neural Inhibition
Phenotype
Seizures
Homeostasis
Biomarkers
Stroke
Brain
Therapeutics

Keywords

  • Amyloid-beta
  • Amyloid-beta precursor protein
  • Fragile X mental retardation protein
  • Fragile X syndrome
  • Hyperexcitability

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Westmark, C. J., Chuang, S. C., Hays, S. A., Filon, M. J., Ray, B. C., Westmark, P. R., ... Wong, R. K. S. (2016). APP causes hyperexcitability in fragile X mice. Frontiers in Molecular Neuroscience, 9(DEC2016), [147]. https://doi.org/10.3389/fnhum.2016.00147

APP causes hyperexcitability in fragile X mice. / Westmark, Cara J.; Chuang, Shih Chieh; Hays, Seth A.; Filon, Mikolaj J.; Ray, Brian C.; Westmark, Pamela R.; Gibson, Jay R.; Huber, Kimberly M.; Wong, Robert K S.

In: Frontiers in Molecular Neuroscience, Vol. 9, No. DEC2016, 147, 15.12.2016.

Research output: Contribution to journalArticle

Westmark, CJ, Chuang, SC, Hays, SA, Filon, MJ, Ray, BC, Westmark, PR, Gibson, JR, Huber, KM & Wong, RKS 2016, 'APP causes hyperexcitability in fragile X mice', Frontiers in Molecular Neuroscience, vol. 9, no. DEC2016, 147. https://doi.org/10.3389/fnhum.2016.00147
Westmark CJ, Chuang SC, Hays SA, Filon MJ, Ray BC, Westmark PR et al. APP causes hyperexcitability in fragile X mice. Frontiers in Molecular Neuroscience. 2016 Dec 15;9(DEC2016). 147. https://doi.org/10.3389/fnhum.2016.00147
Westmark, Cara J. ; Chuang, Shih Chieh ; Hays, Seth A. ; Filon, Mikolaj J. ; Ray, Brian C. ; Westmark, Pamela R. ; Gibson, Jay R. ; Huber, Kimberly M. ; Wong, Robert K S. / APP causes hyperexcitability in fragile X mice. In: Frontiers in Molecular Neuroscience. 2016 ; Vol. 9, No. DEC2016.
@article{8160db9228374249b7933198a1e3fec2,
title = "APP causes hyperexcitability in fragile X mice",
abstract = "Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.",
keywords = "Amyloid-beta, Amyloid-beta precursor protein, Fragile X mental retardation protein, Fragile X syndrome, Hyperexcitability",
author = "Westmark, {Cara J.} and Chuang, {Shih Chieh} and Hays, {Seth A.} and Filon, {Mikolaj J.} and Ray, {Brian C.} and Westmark, {Pamela R.} and Gibson, {Jay R.} and Huber, {Kimberly M.} and Wong, {Robert K S}",
year = "2016",
month = "12",
day = "15",
doi = "10.3389/fnhum.2016.00147",
language = "English (US)",
volume = "9",
journal = "Frontiers in Molecular Neuroscience",
issn = "1662-5099",
publisher = "Frontiers Research Foundation",
number = "DEC2016",

}

TY - JOUR

T1 - APP causes hyperexcitability in fragile X mice

AU - Westmark, Cara J.

AU - Chuang, Shih Chieh

AU - Hays, Seth A.

AU - Filon, Mikolaj J.

AU - Ray, Brian C.

AU - Westmark, Pamela R.

AU - Gibson, Jay R.

AU - Huber, Kimberly M.

AU - Wong, Robert K S

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

AB - Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO/APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO/APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

KW - Amyloid-beta

KW - Amyloid-beta precursor protein

KW - Fragile X mental retardation protein

KW - Fragile X syndrome

KW - Hyperexcitability

UR - http://www.scopus.com/inward/record.url?scp=85007417913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007417913&partnerID=8YFLogxK

U2 - 10.3389/fnhum.2016.00147

DO - 10.3389/fnhum.2016.00147

M3 - Article

C2 - 27064763

AN - SCOPUS:85007417913

VL - 9

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

SN - 1662-5099

IS - DEC2016

M1 - 147

ER -