Dysregulation of mTOR signaling in fragile X syndrome.
Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.
Sharma
Ali
A
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York 10461, USA.
Hoeffer
Charles A
CA
Takayasu
Yukihiro
Y
Miyawaki
Takahiro
T
McBride
Sean M
SM
Klann
Eric
E
Zukin
R Suzanne
RS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039601:Eukaryotic Initiation Factor-4A; D039642:Eukaryotic Initiation Factors; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D018094:Receptors, Metabotropic Glutamate; D012694:Serine; D020123:Sirolimus; C499527:Eif4ebp1 protein, mouse; C497684:Fmr1 protein, mouse; C010117:3,4-dihydroxyphenylglycol