PMID- 21635931
OWN - NLM
STAT- MEDLINE
DCOM- 20120208
LR  - 20220331
IS  - 1878-4216 (Electronic)
IS  - 0278-5846 (Print)
IS  - 0278-5846 (Linking)
VI  - 35
IP  - 7
DP  - 2011 Aug 15
TI  - The mTOR signaling pathway in the prefrontal cortex is compromised in major 
      depressive disorder.
PG  - 1774-9
LID - 10.1016/j.pnpbp.2011.05.010 [doi]
AB  - Recent studies demonstrate that rapid antidepressant response to ketamine is 
      mediated by activation of the mammalian target of rapamycin (mTOR) signaling 
      pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of 
      rats. Our postmortem studies indicate robust deficits in prominent postsynaptic 
      proteins including N-methyl-d-aspartate (NMDA) receptor subunits (NR2A, NR2B), 
      metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic density 
      protein 95kDa (PSD-95) in the PFC in major depressive disorder (MDD). We 
      hypothesize that deficits in the mTOR-dependent translation initiation pathway 
      contribute to the molecular pathology seen in the PFC of MDD subjects, and that a 
      rapid reversal of these abnormalities may underlie antidepressant activity. The 
      majority of known translational regulation occurs at the level of initiation. 
      mTOR regulates translation initiation via its downstream components: p70-kDa 
      ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B 
      (eIF4E and eIF4B). In this study, we examined the expression of mTOR and its core 
      downstream signaling targets: p70S6K, eIF4E, and eIF4B in the PFC of 12 depressed 
      subjects and 12 psychiatrically healthy controls using Western blot. Levels of 
      eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at 
      serine 504 (p-eIF4B-Ser504) were also examined. Adjacent cortical tissue samples 
      from both cohorts of subjects were used in our previous postmortem analyses. 
      There was a significant reduction in mTOR, p70S6K, eIF4B and p-eIF4B protein 
      expression in MDD subjects relative to controls. No group differences were 
      observed in eIF4E, p-eIF4E or actin levels. Our findings show deficits in 
      mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B 
      pathway, and indicate a potential association between marked deficits in synaptic 
      proteins and dysregulation of mTOR signaling in MDD.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Jernigan, Courtney S
AU  - Jernigan CS
AD  - Department of Psychiatry and Human Behavior, University of Mississippi Medical 
      Center, Jackson, MS 39216-4505, USA.
FAU - Goswami, Dharmendra B
AU  - Goswami DB
FAU - Austin, Mark C
AU  - Austin MC
FAU - Iyo, Abiye H
AU  - Iyo AH
FAU - Chandran, Agata
AU  - Chandran A
FAU - Stockmeier, Craig A
AU  - Stockmeier CA
FAU - Karolewicz, Beata
AU  - Karolewicz B
LA  - eng
GR  - P20 RR017701/RR/NCRR NIH HHS/United States
GR  - P20 RR017701-09/RR/NCRR NIH HHS/United States
GR  - RR17701/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110523
PL  - England
TA  - Prog Neuropsychopharmacol Biol Psychiatry
JT  - Progress in neuro-psychopharmacology & biological psychiatry
JID - 8211617
RN  - 0 (Eukaryotic Initiation Factors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Autopsy
MH  - Depressive Disorder, Major/genetics/immunology/*metabolism
MH  - Eukaryotic Initiation Factors/analysis/biosynthesis/genetics/immunology
MH  - Family
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Prefrontal Cortex/immunology/pathology/*physiopathology
MH  - Ribosomal Protein S6 Kinases/analysis/biosynthesis/genetics/immunology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/analysis/biosynthesis/genetics/immunology
MH  - Signal Transduction/genetics/immunology
MH  - TOR Serine-Threonine Kinases/analysis/genetics/immunology/*metabolism
PMC - PMC3154612
MID - NIHMS299502
EDAT- 2011/06/04 06:00
MHDA- 2012/02/09 06:00
PMCR- 2012/08/15
CRDT- 2011/06/04 06:00
PHST- 2011/04/22 00:00 [received]
PHST- 2011/05/17 00:00 [revised]
PHST- 2011/05/17 00:00 [accepted]
PHST- 2011/06/04 06:00 [entrez]
PHST- 2011/06/04 06:00 [pubmed]
PHST- 2012/02/09 06:00 [medline]
PHST- 2012/08/15 00:00 [pmc-release]
AID - S0278-5846(11)00166-7 [pii]
AID - 10.1016/j.pnpbp.2011.05.010 [doi]
PST - ppublish
SO  - Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1774-9. doi: 
      10.1016/j.pnpbp.2011.05.010. Epub 2011 May 23.