Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.
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-beta pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-beta pathway by TGF-beta1 results in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of albumin to TGF-beta receptor II, and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns after BBB breakdown, albumin, and TGF-beta1 exposure, including modulation of genes associated with the TGF-beta pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-beta pathway blockers suppressed most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. Our present data identifies the TGF-beta pathway as a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy.
Cacheaux
Luisa P
LP
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720-3140, USA.
Ivens
Sebastian
S
David
Yaron
Y
Lakhter
Alexander J
AJ
Bar-Klein
Guy
G
Shapira
Michael
M
Heinemann
Uwe
U
Friedman
Alon
A
Kaufer
Daniela
D
D000200:Action Potentials / Q000502:physiology; D000418:Albumins / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D016000:Cluster Analysis; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D004827:Epilepsy / Q000150:complications / Q000209:etiology* / Q000473:pathology; D015870:Gene Expression / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000418:Albumins; D000906:Antibodies; D001549:Benzamides; D004149:Dioxoles; D007473:Ion Channels; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid