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Author Notes:

Correspondence should be addressed to gbassel@emory.edu Gary J. Bassell Department of Cell Biology, Emory University, 615 Michael St., Atlanta, GA 30322, Tel (404) 727-3772, FAX (404) 727-6256

M.N. and X.Y. contributed equally

Subjects:

Research Funding:

National Institute on Drug Abuse : NIDA

National Institute of Mental Health : NIMH

National Institute of Child Health & Human Development : NICHD

This work was supported by a postdoctoral fellowship from NFXF to C.G., NIH MH085617 to G.J.B., NIH HD020521 to S.T.W. and the Fragile X Center, 3P30HD024064 to S.T.W. and G.J.B.

Keywords:

  • FMRP
  • mGluR theory of FXS
  • phosphatidylinositol-3-kinase
  • protein synthesis
  • dendritic spine
  • AMPAR

Excess PI3K subunit synthesis and activity as a novel therapeutic target in Fragile X Syndrome

Tools:

Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 30, Number 32

Publisher:

, Pages 10624-10638

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Fragile X Syndrome (FXS) is an inherited neurologic disease caused by loss of Fragile X Mental Retardation Protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess synaptic activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knockout neurons, excess PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110β, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110β translation, p110β protein expression and PI3K activity. In contrast, both p110β protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knockout. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS-associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS.

Copyright information:

© 2010 the authors

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