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Cell Rep. 2015 May 5;11(5):727-36. doi: 10.1016/j.celrep.2015.03.060. Epub 2015 Apr 23.

Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome.

Author information

1
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: christina.gross@cchmc.org.
2
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Center for Neural Science, New York University, New York, NY 10003, USA.
5
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
7
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: gbassel@emory.edu.

Abstract

The PI3K enhancer PIKE links PI3K catalytic subunits to 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 in FXS.

PMID:
25921541
PMCID:
PMC4418204
DOI:
10.1016/j.celrep.2015.03.060
[Indexed for MEDLINE]
Free PMC Article

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