AUTHOR=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. TITLE=APP Causes Hyperexcitability in Fragile X Mice JOURNAL=Frontiers in Molecular Neuroscience VOLUME=9 YEAR=2016 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2016.00147 DOI=10.3389/fnmol.2016.00147 ISSN=1662-5099 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, Fmr1^KO mice. Normalization of APP levels in Fmr1^KO mice (Fmr1^KO/APP^HET 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 Fmr1^KO brain slices. Fmr1^KO/APP^HET 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 Fmr1^KO 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.