Transcriptome profiling reveals TGF-β signaling involvement in epileptogenesis

Luisa P. Cacheaux, Sebastian Ivens, Yaron David, Alexander J. Lakhter, Guy Bar-Klein, Michael Shapira, Uwe Heinemann, Alon Friedman, Daniela Kaufer

Research output: Contribution to journalArticlepeer-review

251 Scopus citations

Abstract

Brain injury may result in the development of epilepsy, one of the most common neurological disorders. We previously demonstrated that albumin is critical in the generation of epilepsy after blood - brain barrier (BBB) compromise. Here, we identify TGF-β pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-β pathway by TGF-β1 results in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of albumin to TGF-β receptor II, and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns after BBB breakdown, albumin, and TGF-β1 exposure, including modulation of genes associated with the TGF-β pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-β pathway blockers suppressed most albumininduced transcriptional changes and prevented the generation of epileptiform activity. Our present data identifies the TGF-β pathway as a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy.

Original languageEnglish
Pages (from-to)8927-8935
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number28
DOIs
StatePublished - 15 Jul 2009

ASJC Scopus subject areas

  • Neuroscience (all)

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