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

NEUROBIOLOGY OF DISEASE

卷:59

Article

Bernard, Paul B.¹  Castano, Anna M.¹  O'Leary, Heather¹  Simpson, Kameron³  Browning, Michael D.³  Benke, Tim A.^1,2,4,5,6 

[1] Univ Colorado, Sch Med, Dept Pediat, Denver, CO 80202 USA

[2] Univ Colorado, Sch Med, Grad Program Neurosci, Denver, CO 80202 USA

[3] PhosphoSolutions, Aurora, CO USA

[4] Univ Colorado, Sch Med, Dept Neurol, Denver, CO 80202 USA

[5] Univ Colorado, Sch Med, Dept Pharmacol, Denver, CO 80262 USA

[6] Univ Colorado, Sch Med, Dept Otolaryngol, Denver, CO 80202 USA

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

DOI  :  10.1016/j.nbd.2013.06.013

来源: Elsevier

【 摘 要 】

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 synaptosomar compai Unent 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. (C) 2013 Elsevier Inc. All rights reserved.

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