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.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal / physiology*
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Brain / metabolism
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Dendritic Spines / metabolism
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Disease Models, Animal
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Drosophila / metabolism
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Drosophila Proteins / metabolism
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Fragile X Mental Retardation Protein / genetics
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Fragile X Mental Retardation Protein / metabolism
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Fragile X Syndrome / metabolism
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Fragile X Syndrome / pathology*
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GTP Phosphohydrolases / genetics*
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GTP Phosphohydrolases / metabolism*
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GTPase-Activating Proteins / metabolism
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Gene Expression Regulation*
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Mice
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Mice, Knockout
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Mushroom Bodies / metabolism
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism*
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Neuronal Plasticity*
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Biosynthesis
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Receptor, Metabotropic Glutamate 5 / metabolism
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Receptors, Metabotropic Glutamate / metabolism
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Signal Transduction
Substances
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Drosophila Proteins
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Fmr1 protein, mouse
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GTPase-Activating Proteins
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Nerve Tissue Proteins
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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centaurin gamma1A, Drosophila
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metabotropic glutamate receptor type 1
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Fragile X Mental Retardation Protein
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Phosphatidylinositol 3-Kinases
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GTP Phosphohydrolases
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PIKE protein, mouse