title: Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.
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-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.
authors: Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720-3140, USA.
authors: Luisa P
authors: LP
authors: Cacheaux
authors: Sebastian
authors: S
authors: Ivens
authors: Yaron
authors: Y
authors: David
authors: Alexander J
authors: AJ
authors: Lakhter
authors: Guy
authors: G
authors: Bar-Klein
authors: Michael
authors: M
authors: Shapira
authors: Uwe
authors: U
authors: Heinemann
authors: Alon
authors: A
authors: Friedman
authors: Daniela
authors: D
authors: Kaufer
mesh_terms: 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
chemical_list: 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