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

12 Scopus citations

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
StatePublished - Dec 15 2016

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

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