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

59 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Gross, C., Chang, C. W., Kelly, S. M., Bhattacharya, A., McBride, S. M. J., Danielson, S. W., Jiang, M. Q., Chan, C. B., Ye, K., Gibson, J. R., Klann, E., Jongens, T. A., Moberg, K. H., Huber, K. M., & 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