Phosphorylation of FMRP and alterations of FMRP complex underlie enhanced mLTD in adult rats triggered by early life seizures

Neurobiol Dis. 2013 Nov;59:1-17. doi: 10.1016/j.nbd.2013.06.013. Epub 2013 Jul 2.

Abstract

Outside of Fragile X syndrome (FXS), the role of Fragile-X Mental Retardation Protein (FMRP) in mediating neuropsychological abnormalities is not clear. FMRP, p70-S6 kinase (S6K) and protein phosphatase 2A (PP2A) are thought to cooperate as a dynamic signaling complex. In our prior work, adult rats have enhanced CA1 hippocampal long-term depression (LTD) following an early life seizure (ELS). We now show that mGluR-mediated LTD (mLTD) is specifically enhanced following ELS, similar to FMRP knock-outs. Total FMRP expression is unchanged but S6K is hyperphosphorylated, consistent with S6K overactivation. We postulated that either disruption of the FMRP-S6K-PP2A complex and/or removal of this complex from synapses could explain our findings. Using subcellular fractionation, we were surprised to find that concentrations of FMRP and PP2A were undisturbed in the synaptosomal compartment but reduced in parallel in the cytosolic compartment. Following ELS FMRP phosphorylation was reduced in the cytosolic compartment and increased in the synaptic compartment, in parallel with the compartmentalization of S6K activation. Furthermore, FMRP and PP2A remain bound following ELS. In contrast, the interaction of S6K with FMRP is reduced by ELS. Blockade of PP2A results in enhanced mLTD; this is occluded by ELS. This suggests a critical role for the location and function of the FMRP-S6K-PP2A signaling complex in limiting the amount of mLTD. Specifically, non-synaptic targeting and the function of the complex may influence the "set-point" for regulating mLTD. Consistent with this, striatal-enriched protein tyrosine phosphatase (STEP), an FMRP "target" which regulates mLTD expression, is specifically increased in the synaptosomal compartment following ELS. Further, we provide behavioral data to suggest that FMRP complex dysfunction may underlie altered socialization, a symptom associated and observed in other rodent models of autism, including FXS.

Keywords: Fragile X Mental Retardation Protein (FMRP); Long-term depression (LTD); Metabotropic glutamate receptor (mGluR); Protein phosphatase 2A (PP2A); Seizure; Striatal-enriched tyrosine protein phosphatase (STEP).

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / toxicity
  • Female
  • Fragile X Mental Retardation Protein / metabolism*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • In Vitro Techniques
  • Kainic Acid / toxicity
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Phosphorylation
  • Pregnancy
  • Protein Phosphatase 2 / metabolism
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Seizures / chemically induced
  • Seizures / metabolism*
  • Seizures / physiopathology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Subcellular Fractions / metabolism
  • Subcellular Fractions / pathology
  • Thiazoles / pharmacology

Substances

  • 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • Fragile X Mental Retardation Protein
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Protein Phosphatase 2
  • Kainic Acid