PMID- 21867753
OWN - NLM
STAT- MEDLINE
DCOM- 20120723
LR  - 20231213
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 45
IP  - 1
DP  - 2012 Jan
TI  - Decreased CREB levels suppress epilepsy.
PG  - 253-63
LID - 10.1016/j.nbd.2011.08.009 [doi]
AB  - Epilepsy is a common neurologic disorder yet no treatments aimed at preventing 
      epilepsy have been developed. Several molecules including genes containing cAMP 
      response elements (CREs) in their promoters have been identified that contribute 
      to the development of epilepsy, a process called epileptogenesis. When 
      phosphorylated cAMP response element binding protein (CREB) increases 
      transcription from CRE regulated promoters. CREB phosphorylation is increased in 
      rodent epilepsy models, and in the seizure onset region of humans with medically 
      intractable epilepsy (Rakhade et al., 2005; Lee et al., 2007; Lund et al., 2008). 
      Here we show that mice with decreased CREB levels (CREB(alpha∆) mutants) have a ~50% 
      reduction in spontaneous seizures following pilocarpine induced status 
      epilepticus (SE) and require more stimulation to electrically kindle. Following 
      SE, brain derived neurotrophic factor (BDNF) and inducible cAMP early repressor 
      (ICER) mRNAs are differentially up-regulated in the hippocampus and cortex of the 
      CREB(alpha∆) mutants compared to wild-type mice, which may be contributing to 
      differences in the severity of epilepsy. In contrast, we found no difference in 
      KCC2 mRNA levels between the CREB(alpha∆) and wild-type mice after SE. The mechanism 
      by which BDNF and ICER mRNAs increase specifically in the CREB(alpha∆) compared to 
      wild-type mice following SE is not known. We did, however, find an increase in 
      specific cAMP response element modulator (CREM) mRNA transcripts in the CREB(alpha∆) 
      mutants that might be responsible for the differential regulation of BDNF and 
      ICER after SE. Altering CREB activity following a neurologic insult provides a 
      therapeutic strategy for modifying epileptogenesis.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Zhu, Xinjian
AU  - Zhu X
AD  - The Children's Hospital of Philadelphia, Division of Neurology, USA.
FAU - Han, Xiao
AU  - Han X
FAU - Blendy, Julie A
AU  - Blendy JA
FAU - Porter, Brenda E
AU  - Porter BE
LA  - eng
GR  - R01 NS056222/NS/NINDS NIH HHS/United States
GR  - NSR01NS056222/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110810
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Symporters)
RN  - 01MI4Q9DI3 (Pilocarpine)
RN  - 135844-64-3 (Cyclic AMP Response Element Modulator)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Cerebral Cortex/*metabolism
MH  - Cyclic AMP Response Element Modulator/genetics/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/genetics/*metabolism
MH  - Hippocampus/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphorylation
MH  - Pilocarpine
MH  - Seizures/chemically induced/genetics/*metabolism
MH  - Severity of Illness Index
MH  - Status Epilepticus/chemically induced/genetics/*metabolism
MH  - Symporters/genetics/metabolism
MH  - Up-Regulation
MH  - K Cl- Cotransporters
PMC - PMC4011562
MID - NIHMS318412
EDAT- 2011/08/27 06:00
MHDA- 2012/07/24 06:00
PMCR- 2014/05/06
CRDT- 2011/08/27 06:00
PHST- 2011/02/16 00:00 [received]
PHST- 2011/07/27 00:00 [revised]
PHST- 2011/08/03 00:00 [accepted]
PHST- 2011/08/27 06:00 [entrez]
PHST- 2011/08/27 06:00 [pubmed]
PHST- 2012/07/24 06:00 [medline]
PHST- 2014/05/06 00:00 [pmc-release]
AID - S0969-9961(11)00263-4 [pii]
AID - 10.1016/j.nbd.2011.08.009 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2012 Jan;45(1):253-63. doi: 10.1016/j.nbd.2011.08.009. Epub 2011 
      Aug 10.