Brain-derived neurotrophic factor signaling modifies hippocampal gene expression during epileptogenesis in transgenic mice.
Brain-derived neurotrophic factor (BDNF) regulates neuronal survival, differentiation and plasticity. It has been shown to promote epileptogenesis and transgenic mice with decreased and increased BDNF signaling show opposite alterations in epileptogenesis. However, the mechanisms of BDNF action are largely unknown. We studied the gene expression changes 12 days after kainic acid-induced status epilepticus in transgenic mice overexpressing either the functional BDNF receptor trkB or a dominant-negative truncated trkB. Epileptogenesis produced marked changes in expression of 27 of 1090 genes. Cluster analysis revealed BDNF signalling-mediated regulation of functional gene classes involved in cellular transport, DNA repair and cell death, including kinesin motor kinesin family member 3A involved in cellular transport. Furthermore, the expression of cytoskeletal and extracellular matrix components, such as tissue inhibitor of metalloproteinase 2 was altered, emphasizing the importance of intracellular transport and interplay between neurons and glia during epileptogenesis. Finally, mice overexpressing the dominant-negative trkB, which were previously shown to have reduced epileptogenesis, showed a decrease in mRNAs of several growth-associated genes, including growth-associated protein 43. Our data suggest that BDNF signaling may partly mediate the development of epilepsy and propose that regrowth or repair processes initiated by status epilepticus and promoted by BDNF signaling may not be as advantageous as previously thought.
Lähteinen
Sari
S
Laboratory of Molecular Pharmacology, University of Kuopio, PO Box 1627, FIN-70 211 Kuopio, Finland. sari.lahteinen@uku.fi
Pitkänen
Asla
A
Knuuttila
Juha
J
Törönen
Petri
P
Castrén
Eero
E
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D015870:Gene Expression; D006624:Hippocampus / Q000502:physiology*; D017404:In Situ Hybridization, Fluorescence; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000209:etiology / Q000235:genetics*; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D020813:Receptor, trkB; D007608:Kainic Acid