PMID- 20071534
OWN - NLM
STAT- MEDLINE
DCOM- 20100201
LR  - 20231120
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 30
IP  - 2
DP  - 2010 Jan 13
TI  - Dysregulation of mTOR signaling in fragile X syndrome.
PG  - 694-702
LID - 10.1523/JNEUROSCI.3696-09.2010 [doi]
AB  - 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.
FAU - Sharma, Ali
AU  - Sharma A
AD  - Dominick P. Purpura Department of Neuroscience, Albert Einstein College of 
      Medicine, New York, New York 10461, USA.
FAU - Hoeffer, Charles A
AU  - Hoeffer CA
FAU - Takayasu, Yukihiro
AU  - Takayasu Y
FAU - Miyawaki, Takahiro
AU  - Miyawaki T
FAU - McBride, Sean M
AU  - McBride SM
FAU - Klann, Eric
AU  - Klann E
FAU - Zukin, R Suzanne
AU  - Zukin RS
LA  - eng
GR  - NS340007/NS/NINDS NIH HHS/United States
GR  - NS20752/NS/NINDS NIH HHS/United States
GR  - R01 NS047384/NS/NINDS NIH HHS/United States
GR  - NS047384/NS/NINDS NIH HHS/United States
GR  - R01 NS020752/NS/NINDS NIH HHS/United States
GR  - AS2087/AS/Autism Speaks/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Fmr1 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
RN  - 452VLY9402 (Serine)
RN  - 534-82-7 (Methoxyhydroxyphenylglycol)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.7.- (Eukaryotic Initiation Factor-4A)
RN  - UEH9K539KJ (3,4-dihydroxyphenylglycol)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - J Neurosci. 2010 May 26;30(21):7121-3. PMID: 20505079
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - CA1 Region, Hippocampal/metabolism
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Cycle Proteins
MH  - Cognition Disorders/etiology
MH  - Disease Models, Animal
MH  - Eukaryotic Initiation Factor-4A/genetics/metabolism
MH  - Eukaryotic Initiation Factors
MH  - Excitatory Postsynaptic Potentials/drug effects/genetics
MH  - Fragile X Mental Retardation Protein/genetics
MH  - Fragile X Syndrome/*complications/genetics/*metabolism/pathology
MH  - Gene Expression Regulation/drug effects/genetics
MH  - Immunoprecipitation/methods
MH  - In Vitro Techniques
MH  - Long-Term Synaptic Depression/drug effects/genetics
MH  - Methoxyhydroxyphenylglycol/analogs & derivatives/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - Oncogene Protein v-akt/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/genetics/metabolism
MH  - Phosphorylation/genetics
MH  - Receptors, Metabotropic Glutamate/metabolism
MH  - Serine/metabolism
MH  - Signal Transduction/genetics/*physiology
MH  - Sirolimus/*metabolism
PMC - PMC3665010
MID - NIHMS419610
EDAT- 2010/01/15 06:00
MHDA- 2010/02/02 06:00
PMCR- 2010/07/13
CRDT- 2010/01/15 06:00
PHST- 2010/01/15 06:00 [entrez]
PHST- 2010/01/15 06:00 [pubmed]
PHST- 2010/02/02 06:00 [medline]
PHST- 2010/07/13 00:00 [pmc-release]
AID - 30/2/694 [pii]
AID - 3557754 [pii]
AID - 10.1523/JNEUROSCI.3696-09.2010 [doi]
PST - ppublish
SO  - J Neurosci. 2010 Jan 13;30(2):694-702. doi: 10.1523/JNEUROSCI.3696-09.2010.