PMID- 22567115
OWN - NLM
STAT- MEDLINE
DCOM- 20120917
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 5
DP  - 2012
TI  - The interaction between early life epilepsy and autistic-like behavioral 
      consequences: a role for the mammalian target of rapamycin (mTOR) pathway.
PG  - e35885
LID - 10.1371/journal.pone.0035885 [doi]
LID - e35885
AB  - Early life seizures can result in chronic epilepsy, cognitive deficits and 
      behavioral changes such as autism, and conversely epilepsy is common in autistic 
      children. We hypothesized that during early brain development, seizures could 
      alter regulators of synaptic development and underlie the interaction between 
      epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein 
      translation and is dysregulated in Tuberous Sclerosis Complex, a disorder 
      characterized by epilepsy and autism. We used a rodent model of acute 
      hypoxia-induced neonatal seizures that results in long term increases in neuronal 
      excitability, seizure susceptibility, and spontaneous seizures, to determine how 
      seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures 
      occurring at a developmental stage coinciding with a critical period of 
      synaptogenesis will activate mTORC1, contributing to epileptic networks and 
      autistic-like behavior in later life. Here we show that in the rat, baseline 
      mTORC1 activation peaks during the first three postnatal weeks, and induction of 
      seizures at postnatal day 10 results in further transient activation of its 
      downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and 
      phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent 
      upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and 
      phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor 
      rapamycin immediately before and after seizures reversed early increases in 
      glutamatergic neurotransmission and seizure susceptibility and attenuated later 
      life epilepsy and autistic-like behavior. Together, these findings suggest that 
      in the developing brain the mTORC1 signaling pathway is involved in 
      epileptogenesis and altered social behavior, and that it may be a target for 
      development of novel therapies that eliminate the progressive effects of neonatal 
      seizures.
FAU - Talos, Delia M
AU  - Talos DM
AD  - Department of Neurology, Children's Hospital, Boston, Massachusetts, United 
      States of America.
FAU - Sun, Hongyu
AU  - Sun H
FAU - Zhou, Xiangping
AU  - Zhou X
FAU - Fitzgerald, Erin C
AU  - Fitzgerald EC
FAU - Jackson, Michele C
AU  - Jackson MC
FAU - Klein, Peter M
AU  - Klein PM
FAU - Lan, Victor J
AU  - Lan VJ
FAU - Joseph, Annelise
AU  - Joseph A
FAU - Jensen, Frances E
AU  - Jensen FE
LA  - eng
GR  - MFE-115462/CAPMC/CIHR/Canada
GR  - DP1 OD003347/OD/NIH HHS/United States
GR  - T32HD007466/HD/NICHD NIH HHS/United States
GR  - R56 NS031718/NS/NINDS NIH HHS/United States
GR  - T32 HD007466/HD/NICHD NIH HHS/United States
GR  - P30 HD18655/HD/NICHD NIH HHS/United States
GR  - R01 NS 31718/NS/NINDS NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - R01 NS031718/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120502
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - SIV03811UC (Kainic Acid)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/physiology
MH  - Blotting, Western
MH  - Epilepsy/*metabolism/physiopathology
MH  - Immunohistochemistry
MH  - Kainic Acid/pharmacology
MH  - Locomotion/physiology
MH  - Male
MH  - Rats
MH  - Seizures/chemically induced/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3342334
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/05/09 06:00
MHDA- 2012/09/18 06:00
PMCR- 2012/05/02
CRDT- 2012/05/09 06:00
PHST- 2012/01/17 00:00 [received]
PHST- 2012/03/23 00:00 [accepted]
PHST- 2012/05/09 06:00 [entrez]
PHST- 2012/05/09 06:00 [pubmed]
PHST- 2012/09/18 06:00 [medline]
PHST- 2012/05/02 00:00 [pmc-release]
AID - PONE-D-12-02255 [pii]
AID - 10.1371/journal.pone.0035885 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(5):e35885. doi: 10.1371/journal.pone.0035885. Epub 2012 May 2.