title: Astrocyte uncoupling as a cause of human temporal lobe epilepsy.
abstract: Glial cells are now recognized as active communication partners in the central nervous system, and this new perspective has rekindled the question of their role in pathology. In the present study we analysed functional properties of astrocytes in hippocampal specimens from patients with mesial temporal lobe epilepsy without (n = 44) and with sclerosis (n = 75) combining patch clamp recording, K(+) concentration analysis, electroencephalography/video-monitoring, and fate mapping analysis. We found that the hippocampus of patients with mesial temporal lobe epilepsy with sclerosis is completely devoid of bona fide astrocytes and gap junction coupling, whereas coupled astrocytes were abundantly present in non-sclerotic specimens. To decide whether these glial changes represent cause or effect of mesial temporal lobe epilepsy with sclerosis, we developed a mouse model that reproduced key features of human mesial temporal lobe epilepsy with sclerosis. In this model, uncoupling impaired K(+) buffering and temporally preceded apoptotic neuronal death and the generation of spontaneous seizures. Uncoupling was induced through intraperitoneal injection of lipopolysaccharide, prevented in Toll-like receptor4 knockout mice and reproduced in situ through acute cytokine or lipopolysaccharide incubation. Fate mapping confirmed that in the course of mesial temporal lobe epilepsy with sclerosis, astrocytes acquire an atypical functional phenotype and lose coupling. These data suggest that astrocyte dysfunction might be a prime cause of mesial temporal lobe epilepsy with sclerosis and identify novel targets for anti-epileptogenic therapeutic intervention.
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bedner
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dupper
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hüttmann
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Michel K
authors.initials: MK
authors.lastname: Herde
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany Current address: Institute of Neurobiology, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Pavel
authors.initials: P
authors.lastname: Dublin
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Tushar
authors.initials: T
authors.lastname: Deshpande
authors.affiliation: 2 Department of Neurosurgery, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: 3 Experimental Epilepsy Research, Department of Neurosurgery, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Häussler
authors.affiliation: 3 Experimental Epilepsy Research, Department of Neurosurgery, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Carola A
authors.initials: CA
authors.lastname: Haas
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany 4 UCL Institute of Neurology, UCL, London WC1N 3BG, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Henneberger
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Theis
authors.affiliation: 1 Institute of Cellular Neurosciences and Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany Christian.Steinhaeuser@ukb.uni-bonn.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Steinhäuser
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D004569:Electroencephalography / Q000379:methods; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism / Q000473:pathology*; D017629:Gap Junctions / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D012598:Sclerosis / Q000473:pathology; D012640:Seizures / Q000473:pathology* / Q000503:physiopathology
keywords: gap junction coupling; gap junction protein alpha 1; hippocampal sclerosis; inflammation; temporal lobe epilepsy