@article{5fd376989f884cd9bb022a7d0ae3e73a,
title = "Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome",
abstract = "The PI3K enhancer PIKE links PI3K catalytic subunitsto group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects inFXS.",
author = "Christina Gross and Chang, {Chia Wei} and Kelly, {Seth M.} and Aditi Bhattacharya and McBride, {Sean M J} and Danielson, {Scott W.} and Jiang, {Michael Q.} and Chan, {Chi Bun} and Keqiang Ye and Gibson, {Jay R.} and Eric Klann and Jongens, {Thomas A.} and Moberg, {Kenneth H.} and Huber, {Kimberly M.} and Bassell, {Gary J.}",
note = "Funding Information: This research was supported by the FRAXA Research Foundation (C.G., S.M.J.M., and T.A.J.), Brain and Behavior Research Foundation 2012 NARSAD Distinguished Investigator Grant (G.J.B.), Autism Speaks Pilot grant 8293 (C.G.), Charles H. Revson Foundation Senior Biomedical Fellowship (A.B.), University of Pennsylvania R25 MH060490 (Clinical Research Scholars Program in Psychiatry; S.M.J.M.), NIH grants MH105353 (G.J.B. and C.G.), NS045711 (K.M.H.), HD056370 (J.R.G.), NS034007 and NS047384 (E.K.), DOD-Autism (AR1101189; T.A.J.), Emory University Center for Translational Social Neuroscience Pilot Grant (G.J.B.), Emory University Children{\textquoteright}s Center for Neuroscience Pilot Grant (G.J.B. and C.G.), and the Integrated Cellular Imaging Microscopy and Viral Vector Cores of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077. The authors thank Ashwini Poopal and Lindsay Schroeder for technical assistance. We thank Dr. Sharon Swanger for critically reading an earlier version of the manuscript, as well as members of the G.J.B., K.H.M., and K.M.H. labs for discussions. Publisher Copyright: {\textcopyright} 2015 The Authors.",
year = "2015",
doi = "10.1016/j.celrep.2015.03.060",
language = "English (US)",
volume = "11",
pages = "727--736",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}