Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome

Christina Gross, Chia Wei Chang, Seth M. Kelly, Aditi Bhattacharya, Sean M J McBride, Scott W. Danielson, Michael Q. Jiang, Chi Bun Chan, Keqiang Ye, Jay R. Gibson, Eric Klann, Thomas A. Jongens, Kenneth H. Moberg, Kimberly M. Huber, Gary J. Bassell

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)727-736
Number of pages10
JournalCell Reports
Volume11
Issue number5
DOIs
StatePublished - 2015

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Fragile X Syndrome
Neuronal Plasticity
Phosphatidylinositol 3-Kinases
Plasticity
Diptera
Defects
Metabotropic Glutamate 5 Receptor
Mushroom Bodies
Short-Term Memory
Mental Disorders
Intellectual Disability
Drosophila
Data storage equipment
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Gross, C., Chang, C. W., Kelly, S. M., Bhattacharya, A., McBride, S. M. J., Danielson, S. W., ... Bassell, G. J. (2015). Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome. Cell Reports, 11(5), 727-736. https://doi.org/10.1016/j.celrep.2015.03.060

Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome. / Gross, Christina; Chang, Chia Wei; Kelly, Seth M.; Bhattacharya, Aditi; McBride, Sean M J; Danielson, Scott W.; Jiang, Michael Q.; Chan, Chi Bun; Ye, Keqiang; Gibson, Jay R.; Klann, Eric; Jongens, Thomas A.; Moberg, Kenneth H.; Huber, Kimberly M.; Bassell, Gary J.

In: Cell Reports, Vol. 11, No. 5, 2015, p. 727-736.

Research output: Contribution to journalArticle

Gross, C, Chang, CW, Kelly, SM, Bhattacharya, A, McBride, SMJ, Danielson, SW, Jiang, MQ, Chan, CB, Ye, K, Gibson, JR, Klann, E, Jongens, TA, Moberg, KH, Huber, KM & Bassell, GJ 2015, 'Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome', Cell Reports, vol. 11, no. 5, pp. 727-736. https://doi.org/10.1016/j.celrep.2015.03.060
Gross, Christina ; Chang, Chia Wei ; Kelly, Seth M. ; Bhattacharya, Aditi ; McBride, Sean M J ; Danielson, Scott W. ; Jiang, Michael Q. ; Chan, Chi Bun ; Ye, Keqiang ; Gibson, Jay R. ; Klann, Eric ; Jongens, Thomas A. ; Moberg, Kenneth H. ; Huber, Kimberly M. ; Bassell, Gary J. / Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome. In: Cell Reports. 2015 ; Vol. 11, No. 5. pp. 727-736.
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AU - Gibson, Jay R.

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AU - Jongens, Thomas A.

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