PMID- 23479645
OWN - NLM
STAT- MEDLINE
DCOM- 20130523
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 13
DP  - 2013 Mar 26
TI  - Mammalian target of rapamycin complex 1 activation negatively regulates Polo-like 
      kinase 2-mediated homeostatic compensation following neonatal seizures.
PG  - 5199-204
LID - 10.1073/pnas.1208010110 [doi]
AB  - Homeostatic plasticity is characterized by compensatory changes in synaptic 
      strength and intrinsic membrane properties in response to chronic changes in 
      neuronal activity. Neonatal seizures are a naturally occurring source of neuronal 
      overactivation and can lead to long-term epilepsy and cognitive deficits. Using a 
      rodent model of hypoxia-induced neonatal seizures that results in a persistent 
      increase in AMPA receptor (AMPAR) function in hippocampal CA1 pyramidal neurons, 
      we aimed to determine whether there was any evidence of an opposing endogenous 
      homeostatic antiepileptic response. Given that this model results in long-term 
      epilepsy, we also examined mechanisms whereby this homeostasis fails. Whole-cell 
      patch-clamp recordings from neurons in slices removed at intervals following 
      seizure onset revealed an initial up-regulation of AMPAR function that was 
      followed by a transient dynamic attenuation of this enhancement by 48-72 h, 
      although AMPAR function was still increased compared with nonseizure control 
      baseline. This secondary down-regulation of enhanced AMPAR function was 
      coincident with a marked transient increase in expression and function of the 
      Polo-like kinase 2 (PLK2), which has previously been implicated in homeostatic 
      down-regulation of neuronal excitability in cell/slice culture models. The 
      effects were transient and at 1 wk AMPAR function once again became up-regulated, 
      simultaneous with a decrease in PLK2 expression and function. This negative 
      regulation was mediated by subacute postseizure increases in mammalian target of 
      rapamycin (mTOR). Application of the mTOR inhibitor rapamycin prevented 
      post-hypoxic seizure impairment of homeostasis, suggesting that homeostatic 
      plasticity mechanisms may be potentially modifiable therapeutic targets in 
      epileptogenesis.
FAU - Sun, Hongyu
AU  - Sun H
AD  - Department of Neurology, Division of Neuroscience, Children's Hospital and 
      Harvard Medical School, Boston, MA 02115, USA.
FAU - Kosaras, Bela
AU  - Kosaras B
FAU - Klein, Peter M
AU  - Klein PM
FAU - Jensen, Frances E
AU  - Jensen FE
LA  - eng
GR  - MFE-115462/CAPMC/CIHR/Canada
GR  - DP1 OD003347/OD/NIH HHS/United States
GR  - R56 NS031718/NS/NINDS 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 - 20130311
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Receptors, AMPA)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.21 (Plk2 protein, rat)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Anti-Bacterial Agents/pharmacology
MH  - CA1 Region, Hippocampal/*metabolism/pathology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Microdissection
MH  - Multiprotein Complexes
MH  - *Neuronal Plasticity
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proteins/antagonists & inhibitors/metabolism
MH  - Pyramidal Cells/*metabolism/pathology
MH  - Rats
MH  - Rats, Long-Evans
MH  - Receptors, AMPA/metabolism
MH  - Seizures/*metabolism/pathology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Time Factors
MH  - Tissue Culture Techniques
PMC - PMC3612683
COIS- The authors declare no conflict of interest.
EDAT- 2013/03/13 06:00
MHDA- 2013/05/25 06:00
PMCR- 2013/09/26
CRDT- 2013/03/13 06:00
PHST- 2013/03/13 06:00 [entrez]
PHST- 2013/03/13 06:00 [pubmed]
PHST- 2013/05/25 06:00 [medline]
PHST- 2013/09/26 00:00 [pmc-release]
AID - 1208010110 [pii]
AID - 201208010 [pii]
AID - 10.1073/pnas.1208010110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5199-204. doi: 
      10.1073/pnas.1208010110. Epub 2013 Mar 11.