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Neuronal and Glial Mechanisms Underlying BBB Dysfunction-Induced Epileptogenesis

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Neuronal and Glial Mechanisms Underlying BBB Dysfunction-Induced Epileptogenesis Neuronal and Glial Mechanisms Underlying BBB Dysfunction-Induced Epileptogenesis Thesis submitted in partial fulfillment of the requirements for the degree of “DOCTOR OF PHILOSOPHY” by Yaron David Submitted to the Senate of Ben-Gurion University of the Negev November 2011 Beer-Sheva Neuronal and Glial Mechanisms Underlying BBB Dysfunction-Induced Epileptogenesis Thesis submitted in partial fulfillment of the requirements for the degree of “DOCTOR OF PHILOSOPHY” by Yaron David Submitted to the Senate of Ben-Gurion University of the Negev Approved by the advisor_________ Approved by the Dean of the Kreitman School of Advanced Graduate Studies_______ November 2011 Beer-Sheva This work was carried out under the supervision of Professor Alon Friedman The department of Physiology, Faculty of Health Sciences Ben-Gurion University of the Negev. First and foremost, I would like to thank my mentor, Prof. Alon Friedman, who offered an opportunity to a young student who knew absolutely nothing in the field of neuroscience. Your enthusiasm for the pursuit of knowledge is contagious. I also thank you for being a friend. I would like to thanks all those people I encountered throughout the years: Oren Tomkins who brought me to the lab. Uwe Heinemann who kindly opened the gates of the Institute fur Physiologie, in Berlin for me. Sebastian Ivens, for teaching me electrophysiology and being a good friend. Daniela Kaufer and Luisa P. Flores from UC Berkley, without whom I am sure I wouldn‘t have any molecular studies to present. Ilya Fleidervish, with whom every hour is like a semester of teaching. Maya Ketzef, a good friend which never ceases to help me and others. To my many friends in the Beer-Sheva lab: Ofer Prager, Itai Weissberg, Lyn Kamintsky, Jonathan Cohen, Yehudit Gnatek and Nitzan Levi. People in the Charite lab: Ezequiel Lapilover, Karl Schoknecht and Aljoscha Reichert. And finally, to the many animals that helped my research along the years. I dedicate this to my dear family, Lea and Hezi my parents and my loving wife, Yifat. Without whom none of this would have happened. Contents 1. Abstract ................................................................................................................................9 2. Introduction ........................................................................................................................12 2.1. Overview .....................................................................................................................12 2.2. The Blood Brain Barrier in Health and Disease .........................................................12 2.3. Insult Induced Epilepsy...............................................................................................14 3. Results ................................................................................................................................17 3.1. Transcriptome Profiling Reveals TGF-Β Signaling Involvement in Epileptogenesis 17 3.2. Astrocytic Dysfunction in Epileptogenesis: Consequences of Altered Potassium and Glutamate Homeostasis? ........................................................................................................43 3.3. Blood Brain Barrier Dysfunction Underlies Stroke Complications ...........................77 3.4. The Axon Initial Segment of Layer 5 Pyramidal Neurons Following Stroke ..........105 4. Discussion and Conclusions .............................................................................................127 5. Bibliography .....................................................................................................................131 6. List of Publications...........................................................................................................140 142......................................................................................................................... תקציר .7 List of figures Figure 2.1:‎ Structure of the Blood-Brain Barrier. ............................................................. 13 Figure 4.1:‎ Pathogenesis of BBB disruption mediated epileptogenesis. ........................ 127 List of abbreviations AIS Axon initial segment BBB Blood-Brain Barrier BSA Bovine Serum Albumin CCD Charge-coupled device CNS Central Nervous System DOC Deoxycholic Acid EPSC Excitatory Post Synaptic Current EPSP Excitatory Post Synaptic Potential FDR False Discovery Rate GFAP Glial Fibrillary Acidic Protein GO Gene Ontology LED Light Emitting Diode MCAo Medial Cerebral Artery Occlusion mRNA Messanger RiboNucleic Acid qRT-PCR Quantitative Real Time Polymerase Chain Reaction RBG Rose Bengal REST Relative Expression Software Tool SAM Significance analysis of microarrays SBFI Sodium-Binding Benzofuran Isophthalate SLE Seizure Like Events SMAD Mothers Against Decapentaplegic Homolog TGF-β Transforming Growth Factor beta TJ Tight Junction 1. Abstract Epilepsy is a common disease of the central nervous system, characterized by the paroxysmal appearance of multiple seizures. Even today, despite our growing understanding of the disease, epilepsy remains an incurable, only partially controlled disease. Epilepsy often develops following insults to the brain, including traumatic brain injuries, ischemia, infections, and tumors. Even today, the exact mechanisms underlying epileptogenesis, i.e., the process by which the healthy brain becomes epileptic, are not known, and there are at present no means to prevent it. Interestingly, in many (if not all) of the epileptogenic insults, vascular pathologies have been described, blood brain barrier (BBB) dysfunction in particular. The BBB is an anatomical and functional barrier that enables the central nervous system to maintain a tightly controlled environment, acting to limit the entry of blood-borne constituents into the brain‘s extracellular space. Recent studies from our laboratory demonstrated that BBB dysfunction is sufficient to induce recurrent paroxysmal epileptiform activity and seizures. Furthermore, it was shown that the penetration into the brain‘s parenchyma of a common blood protein, albumin, is sufficient to induce epileptogenesis, with one experiment suggesting this is mediated through the activation of the Transforming Growth Factor beta (TGF-) signaling pathway. The main goal of this thesis was to study the mechanisms by which BBB dysfunction induces epileptogenesis. In my work, I have found that, indeed, direct activation of the TGF-β pathway by the cytokine TGF-β1 results in the appearance of epileptiform activity similar to that observed after brain exposure to albumin. Co-immunoprecipitation revealed binding of albumin to TGF-β receptor II, and Smad2 phosphorylation following cortical application of albumin confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns across large gene groups following both BBB breakdown, and the cortical application of albumin or TGF-β1. Gene changes encompassed genes associated with the TGF-β pathway, 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. - 9 - As one of the earliest events observed following either albumin application or other cortical lesions, is the rapid up-regulation the glial fibrillary acidic protein (GFAP), which is found exclusively in astrocytes, in the second part of my work, I investigated the role of astrocytes in our animal model. I have found similar, robust changes in astrocytic gene expression coding for genes associated with potassium and glutamate homeostasis. These changes predict reduced astrocytic clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. To investigate the consequences of reduced astrocytic uptake of potassium and glutamate on excitatory postsynaptic potentials (EPSPs) I used a computer simulation built within the NEURON environment. Using computer modeling, we predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of synaptic potentials, while potassium accumulation leads to frequency-dependent (10–50 Hz) and N- methyl-D-aspartic acid (NMDA)-dependent synaptic facilitation. In vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity preferentially occurring with stimulation frequencies around 20 Hz. In summary, these data indicate a transcription-mediated astrocytic transformation early during epileptogenesis and suggests that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyper-excitability and network synchronization. As BBB dysfunction is commonly observed in the ischemic brain, we explored the role of BBB dysfunction in the pathogenesis of stroke using imaging experiments in the photothrombosis model, exploration of mRNA expression data obtained from rat brains exposed to medial cerebral artery occlusion, and electrophysiological recordings. We observed rapid changes in gene expression following the ischemic insult leading to delayed dysfunction of the BBB surrounding the infarcted brain. Hyperexcitability and seizure like activity appeared only a few days following the ischemic event. We propose
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