Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis

被引:284
作者
Cacheaux, Luisa P. [2 ]
Ivens, Sebastian [3 ]
David, Yaron [4 ,5 ]
Lakhter, Alexander J. [4 ,5 ]
Bar-Klein, Guy [4 ,5 ]
Shapira, Michael [1 ]
Heinemann, Uwe [3 ]
Friedman, Alon [3 ,4 ,5 ]
Kaufer, Daniela [1 ,2 ]
机构
[1] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA
[3] Charite, Inst Neurophysiol, D-10117 Berlin, Germany
[4] Ben Gurion Univ Negev, Dept Physiol, Zlotowski Ctr Neurosci, IL-84105 Beer Sheva, Israel
[5] Ben Gurion Univ Negev, Dept Neurosurg, Zlotowski Ctr Neurosci, IL-84105 Beer Sheva, Israel
基金
以色列科学基金会;
关键词
BLOOD-BRAIN-BARRIER; TEMPORAL-LOBE EPILEPSY; NECROSIS-FACTOR-ALPHA; FACTOR-KAPPA-B; TRANSFORMING GROWTH-FACTOR-BETA-1; NEOCORTICAL EPILEPTOGENESIS; ALZHEIMERS-DISEASE; STATUS EPILEPTICUS; RAT HIPPOCAMPUS; IN-VIVO;
D O I
10.1523/JNEUROSCI.0430-09.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-beta 1 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-beta 1 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.
引用
收藏
页码:8927 / 8935
页数:9
相关论文
共 46 条
[1]   Astrocyte-endothelial interactions at the blood-brain barrier [J].
Abbott, NJ ;
Rönnbäck, L ;
Hansson, E .
NATURE REVIEWS NEUROSCIENCE, 2006, 7 (01) :41-53
[2]   A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β [J].
Balosso, Silvia ;
Maroso, Mattia ;
Sanchez-Alavez, Manuel ;
Ravizza, Teresa ;
Frasca, Angelisa ;
Bartfai, Tamas ;
Vezzani, Annamaria .
BRAIN, 2008, 131 :3256-3265
[3]   Control of synaptic strength by glial TNFα [J].
Beattie, EC ;
Stellwagen, D ;
Morishita, W ;
Bresnahan, JC ;
Ha, BK ;
Von Zastrow, M ;
Beattie, MS ;
Malenka, RC .
SCIENCE, 2002, 295 (5563) :2282-2285
[4]   Production of monocyte chemotactic protein-1 by rat brain macrophages [J].
Calvo, CF ;
Yoshimura, T ;
Gelman, M ;
Mallat, M .
EUROPEAN JOURNAL OF NEUROSCIENCE, 1996, 8 (08) :1725-1734
[5]   Interleukin-1β activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo:: Implications for Alzheimer's disease [J].
Casamenti, F ;
Prosperi, C ;
Scali, C ;
Giovannelli, L ;
Colivicchi, MA ;
Faussone-Pellegrini, MS ;
Pepeu, G .
NEUROSCIENCE, 1999, 91 (03) :831-842
[6]   Upregulation of gp130 and differential activation of STAT and p42/44 MAPK in the rat hippocampus following kainic acid-induced seizures [J].
Choi, JS ;
Kim, SY ;
Park, HJ ;
Cha, HJ ;
Choi, YS ;
Kang, JE ;
Chung, JW ;
Chun, MH ;
Lee, MY .
MOLECULAR BRAIN RESEARCH, 2003, 119 (01) :10-18
[7]   ELECTRO-PHYSIOLOGICAL PROPERTIES OF NEOCORTICAL NEURONS INVITRO [J].
CONNORS, BW ;
GUTNICK, MJ ;
PRINCE, DA .
JOURNAL OF NEUROPHYSIOLOGY, 1982, 48 (06) :1302-1320
[8]  
Cornford E M, 1999, Adv Neurol, V79, P845
[9]  
Cornford E M, 1986, Adv Neurol, V44, P787
[10]   DAVID: Database for annotation, visualization, and integrated discovery [J].
Dennis, G ;
Sherman, BT ;
Hosack, DA ;
Yang, J ;
Gao, W ;
Lane, HC ;
Lempicki, RA .
GENOME BIOLOGY, 2003, 4 (09)