@article{3e687695f7a64228b5e7dc74c0eadc39,
title = "Selective Role of the Catalytic PI3K Subunit p110β in Impaired Higher Order Cognition in Fragile X Syndrome",
abstract = "Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition.",
author = "Christina Gross and Nisha Raj and Gemma Molinaro and Allen, {Amanda G.} and Whyte, {Alonzo J.} and Gibson, {Jay R.} and Huber, {Kimberly M.} and Gourley, {Shannon L.} and Bassell, {Gary J.}",
note = "Funding Information: This research was supported by the FRAXA Research Foundation (C.G.), Brain and Behavior Research Foundation 2012 NARSAD Distinguished Investigator Grant (G.J.B.), Autism Speaks Pilot Grant 8293 (C.G.), NIH grants MH103748 (C.G.), NS045711 (K.M.H.), and HD056370 (J.R.G.), 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., S.L.G., C.G.), and the Integrated Cellular Imaging Microscopy and Viral Vector Cores of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077. Work performed at the Yerkes National Primate Research Center was supported by the Office of Research Infrastructure Programs/OD P51OD11132. We thank Dr. Richard Paylor for providing written details on the method of audiogenic seizures and Dr. Gretchen Neigh for help with the marble burying assays. The authors thank Ashwini Poopal, Michael Kraetz, John Yamin, Lindsay Schroeder, and the Confocal Imaging Core at CCHMC for technical assistance and Dr. Robert Nussbaum for p110β heterozygous mice. We thank Dr. Sharon Swanger for critically reading an earlier version of the manuscript and members of the G.J.B. and S.L.G. labs for discussions. Publisher Copyright: {\textcopyright} 2015 The Authors.",
year = "2015",
doi = "10.1016/j.celrep.2015.03.065",
language = "English (US)",
volume = "11",
pages = "681--688",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}