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,Fmr1KOmice. Normalization of APP levels inFmr1KOmice (Fmr1KO/APPHETmice) 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 inFmr1KObrain slices.Fmr1KO/APPHETslices 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 mGluR5and FMRP. Both over- and under-expression of APP in the context of theFmr1KOincreases 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.
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison Madison, WI, USA.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Westmark
authors.affiliation: Department of Physiology and Pharmacology, State University of New York Downstate Medical Center Brooklyn, NY, USA.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chuang
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Hays
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison Madison, WI, USA.
authors.forename: Mikolaj J
authors.initials: MJ
authors.lastname: Filon
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison Madison, WI, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ray
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison Madison, WI, USA.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Westmark
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Gibson
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
authors.affiliation: Department of Physiology and Pharmacology, State University of New York Downstate Medical Center Brooklyn, NY, USA.
authors.forename: Robert K S
authors.initials: RK
authors.lastname: Wong
keywords: amyloid-beta; amyloid-beta precursor protein; fragile X mental retardation protein; fragile X syndrome; hyperexcitability