title: Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?
abstract: Focal epilepsy often develops following traumatic, ischemic, or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood-brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid upregulation of the astrocytic marker GFAP (glial fibrillary acidic protein), followed by delayed (within 4-7 d) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings in vitro confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on EPSPs. The model predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10-50 Hz) and NMDA-dependent synaptic facilitation. In vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyperexcitability and network synchronization.
authors.affiliation: Department of Physiology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: David
authors.forename: Luisa P
authors.initials: LP
authors.lastname: Cacheaux
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ivens
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Lapilover
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaufer
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
mesh_terms: D000418:Albumins; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003198:Computer Simulation; D003840:Deoxycholic Acid / Q000633:toxicity; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008959:Models, Neurological; D019579:Neocortex / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000418:Albumins; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D003840:Deoxycholic Acid; D018698:Glutamic Acid; D011188:Potassium