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The Journal of Neuroscience, July 15, 2009, 29(28):8927-8935; doi:10.1523/JNEUROSCI.0430-09.2009

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Neurobiology of Disease
Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis

Luisa P. Cacheaux,¹ Sebastian Ivens,³ Yaron David,⁴ Alexander J. Lakhter,⁴ Guy Bar-Klein,⁴ Michael Shapira,² Uwe Heinemann,³ Alon Friedman,^3,4 and Daniela Kaufer^1,2

¹Helen Wills Neuroscience Institute and ²Department of Integrative Biology, University of California, Berkeley, Berkeley, California 94720-3140, ³Institute of Neurophysiology, Charité University Medicine, 10117 Berlin, Germany, and ⁴Departments of Physiology and Neurosurgery, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

Correspondence should be addressed to Prof. Daniela Kaufer, Department of Integrative Biology, 3060 Valley Life Sciences Building, University of California, Berkeley, Berkeley, CA 94720-3140. Email: danielak{at}berkeley.edu

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 albumin-induced 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.

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Received Jan. 21, 2009; revised May 15, 2009; accepted June 3, 2009.

Correspondence should be addressed to Prof. Daniela Kaufer, Department of Integrative Biology, 3060 Valley Life Sciences Building, University of California, Berkeley, Berkeley, CA 94720-3140. Email: danielak{at}berkeley.edu

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				Y. David, L. P. Cacheaux, S. Ivens, E. Lapilover, U. Heinemann, D. Kaufer, and A. Friedman Astrocytic Dysfunction in Epileptogenesis: Consequence of Altered Potassium and Glutamate Homeostasis? J. Neurosci., August 26, 2009; 29(34): 10588 - 10599. [Abstract] [Full Text] [PDF]

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