A common pattern of persistent gene activation in human neocortical epileptic foci.
Epilepsy is a disease of recurrent seizures that can develop after a wide range of brain insults. Although surgical resection of focal regions of seizure onset can result in clinical improvement, the molecular mechanisms that produce and maintain focal hyperexcitability are not understood. Here, we demonstrate a regional, persistent induction of a common group of genes in human epileptic neocortex in 17 patients with neocortical epilepsy, regardless of the underlying pathology. This relatively small group of common genes, identified using complementary DNA microarrays and confirmed with quantitative reverse transcription polymerase chain reaction and immunostaining, include the immediate early gene transcription factors EGR-1, EGR-2, and c-fos, with roles in learning and memory, and signaling genes such as the dual-specificity kinase/phosphatase MKP-3. Maximal expression of these genes was observed in neurons in neocortical layers II through IV. These neurons also showed persistent cyclic adenosine monophosphate response element binding protein (CREB) activation and nuclear translocation of EGR-2 and c-fos proteins. In two patients, local interictal epileptiform discharge frequencies correlated precisely with the expression of these genes, suggesting that these genes either are directly modulated by the degree of epileptic activity or help sustain ongoing epileptic activity. The identification of a common set of genes and the persistent activation of CREB signaling in human epileptic foci provide a clinically relevant set of biological markers with potential importance for developing future diagnostic and therapeutic options in human epilepsy.
Rakhade
Sanjay N
SN
Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA.
Yao
Bin
B
Ahmed
Sharlin
S
Asano
Eishi
E
Beaumont
Thomas L
TL
Shah
Aashit K
AK
Draghici
Sorin
S
Krauss
Raul
R
Chugani
Harry T
HT
Sood
Sandeep
S
Loeb
Jeffrey A
JA
D000293:Adolescent; D001931:Brain Mapping; D002648:Child; D002675:Child, Preschool; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D017781:Genes, Immediate-Early / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007211:Indoles; D007223:Infant; D008297:Male; D019579:Neocortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011336:Probability; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C007293:DAPI