PMID- 19553465
OWN - NLM
STAT- MEDLINE
DCOM- 20090804
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 29
IP  - 25
DP  - 2009 Jun 24
TI  - Inhibition of the mammalian target of rapamycin signaling pathway suppresses 
      dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy.
PG  - 8259-69
LID - 10.1523/JNEUROSCI.4179-08.2009 [doi]
AB  - Dentate granule cell axon (mossy fiber) sprouting is a common abnormality in 
      patients with temporal lobe epilepsy. Mossy fiber sprouting creates an aberrant 
      positive-feedback network among granule cells that does not normally exist. Its 
      role in epileptogenesis is unclear and controversial. If it were possible to 
      block mossy fiber sprouting from developing after epileptogenic treatments, its 
      potential role in the pathogenesis of epilepsy could be tested. Previous attempts 
      to block mossy fiber sprouting have been unsuccessful. The present study targeted 
      the mammalian target of rapamycin (mTOR) signaling pathway, which regulates cell 
      growth and is blocked by rapamycin. Rapamycin was focally, continuously, and 
      unilaterally infused into the dorsal hippocampus for prolonged periods beginning 
      within hours after rats sustained pilocarpine-induced status epilepticus. 
      Infusion for 1 month reduced aberrant Timm staining (a marker of mossy fibers) in 
      the granule cell layer and molecular layer. Infusion for 2 months inhibited mossy 
      fiber sprouting more. However, after rapamycin infusion ceased, aberrant Timm 
      staining developed and approached untreated levels. When onset of infusion began 
      after mossy fiber sprouting had developed for 2 months, rapamycin did not reverse 
      aberrant Timm staining. These findings suggest that inhibition of the mTOR 
      signaling pathway suppressed development of mossy fiber sprouting. However, 
      suppression required continual treatment, and rapamycin treatment did not reverse 
      already established axon reorganization.
FAU - Buckmaster, Paul S
AU  - Buckmaster PS
AD  - Department of Comparative Medicine, Stanford University, Stanford, California 
      94305, USA. psb@stanford.edu
FAU - Ingram, Elizabeth A
AU  - Ingram EA
FAU - Wen, Xiling
AU  - Wen X
LA  - eng
GR  - T35 RR017188/RR/NCRR NIH HHS/United States
GR  - T35 RR017188-08/RR/NCRR NIH HHS/United States
GR  - R01 NS039110-10/NS/NINDS NIH HHS/United States
GR  - R01 NS040276-09/NS/NINDS NIH HHS/United States
GR  - R01 NS039110/NS/NINDS NIH HHS/United States
GR  - R01 NS040276/NS/NINDS NIH HHS/United States
GR  - T35 OD010989/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Anticonvulsants)
RN  - 0 (Atropine Derivatives)
RN  - 0 (Muscarinic Agonists)
RN  - 0 (Parasympatholytics)
RN  - 01MI4Q9DI3 (Pilocarpine)
RN  - 80719I460H (methylatropine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/administration & dosage/*pharmacology
MH  - Atropine Derivatives/administration & dosage/pharmacology
MH  - Axons/drug effects/metabolism/pathology
MH  - Dentate Gyrus/*pathology/physiopathology
MH  - Disease Models, Animal
MH  - Epilepsy, Temporal Lobe/chemically induced/*physiopathology/prevention & control
MH  - Immunohistochemistry
MH  - Infusions, Parenteral
MH  - Injections, Intraperitoneal
MH  - Male
MH  - Mossy Fibers, Hippocampal/drug effects/*pathology/physiopathology
MH  - Muscarinic Agonists/administration & dosage/pharmacology
MH  - Neural Inhibition/drug effects
MH  - Neurons/drug effects/*metabolism/pathology
MH  - Parasympatholytics/administration & dosage/pharmacology
MH  - Pilocarpine/administration & dosage/pharmacology
MH  - Protein Kinases/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage/*pharmacology
MH  - Staining and Labeling
MH  - Status Epilepticus/*chemically induced/physiopathology/prevention & control
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
PMC - PMC2819377
MID - NIHMS173373
EDAT- 2009/06/26 09:00
MHDA- 2009/08/06 09:00
PMCR- 2009/12/24
CRDT- 2009/06/26 09:00
PHST- 2009/06/26 09:00 [entrez]
PHST- 2009/06/26 09:00 [pubmed]
PHST- 2009/08/06 09:00 [medline]
PHST- 2009/12/24 00:00 [pmc-release]
AID - 29/25/8259 [pii]
AID - 3461447 [pii]
AID - 10.1523/JNEUROSCI.4179-08.2009 [doi]
PST - ppublish
SO  - J Neurosci. 2009 Jun 24;29(25):8259-69. doi: 10.1523/JNEUROSCI.4179-08.2009.