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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Brain / metabolism
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Drosophila / metabolism
  • Drosophila Proteins / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / pathology*
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism*
  • GTPase-Activating Proteins / metabolism
  • Gene Expression Regulation*
  • Mice
  • Mice, Knockout
  • Mushroom Bodies / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Biosynthesis
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Signal Transduction

Substances

  • Drosophila Proteins
  • Fmr1 protein, mouse
  • GTPase-Activating Proteins
  • Nerve Tissue Proteins
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • centaurin gamma1A, Drosophila
  • metabotropic glutamate receptor type 1
  • Fragile X Mental Retardation Protein
  • Phosphatidylinositol 3-Kinases
  • GTP Phosphohydrolases
  • PIKE protein, mouse