Document Detail


Layer-specific CREB target gene induction in human neocortical epilepsy.
MedLine Citation:
PMID:  23055509     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Epilepsy is a disorder of recurrent seizures that affects 1% of the population. To understand why some areas of cerebral cortex produce seizures and others do not, we identified differentially expressed genes in human epileptic neocortex compared with nearby regions that did not produce seizures. The transcriptome that emerged strongly implicates MAPK signaling and CREB-dependent transcription, with 74% of differentially expressed genes containing a cAMP response element (CRE) in their proximal promoter, more than half of which are conserved. Despite the absence of recent seizures in these patients, epileptic brain regions prone to seizures showed persistent activation of ERK and CREB. Persistent CREB activation was directly linked to CREB-dependent gene transcription by chromatin immunoprecipitation that showed phosphorylated CREB constitutively associated with the proximal promoters of many of the induced target genes involved in neuronal signaling, excitability, and synaptic plasticity. A distinct spatial pattern of ERK activation was seen in superficial axodendritic processes of epileptic neocortex that colocalized with both CREB phosphorylation and CREB target gene induction in well demarcated populations of layer 2/3 neurons. These same neuronal lamina showed a marked increase in synaptic density. The findings generated in this study generate a robust and spatially restricted pattern of epileptic biomarkers and associated synaptic changes that could lead to new mechanistic insights and potential therapeutic targets for human epilepsy.
Authors:
Thomas L Beaumont; Bin Yao; Aashit Shah; Gregory Kapatos; Jeffrey A Loeb
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-11     Completed Date:  2013-01-03     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14389-401     Citation Subset:  IM    
Affiliation:
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Child
Child, Preschool
Cyclic AMP Response Element-Binding Protein / biosynthesis*,  genetics
Epilepsy / genetics*,  metabolism*
Female
Gene Expression Regulation*
Gene Targeting* / methods
Humans
Male
Middle Aged
Neocortex / cytology,  physiology*
Reaction Time / genetics
Transcription, Genetic / physiology
Grant Support
ID/Acronym/Agency:
F30NS049776/NS/NINDS NIH HHS; R01 NS045207/NS/NINDS NIH HHS; R01 NS058802/NS/NINDS NIH HHS; R01NS045207/NS/NINDS NIH HHS; R01NS058802/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/CREB1 protein, human; 0/Cyclic AMP Response Element-Binding Protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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