title: Epileptiform activity and spreading depolarization in the blood-brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity.
abstract: Peri-infarct opening of the blood-brain barrier may be associated with spreading depolarizations, seizures, and epileptogenesis as well as cognitive dysfunction. We aimed to investigate the mechanisms underlying neural network pathophysiology in the blood-brain barrier-dysfunctional hippocampus. Photothrombotic stroke within the rat neocortex was associated with increased intracranial pressure, vasogenic edema, and peri-ischemic blood-brain barrier dysfunction that included the ipsilateral hippocampus. Intrahippocampal recordings revealed electrographic seizures within the first week in two-thirds of animals, accompanied by a reduction in gamma and increase in theta frequency bands. Synaptic interactions were studied in parasagittal hippocampal slices at 24 h and seven days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes, and spreading depolarizations at 24 h. Input-output analysis revealed that fEPSP-spike coupling was significantly enhanced at seven days. In addition, CA1 feedback and feedforward inhibition were diminished. Slices generating epileptiform activity at seven days revealed impaired bidirectional long-term plasticity following high and low-frequency stimulation protocols. Microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABAA-receptor subunits. We conclude that blood-brain barrier dysfunction in the peri-infarct hippocampus is associated with early disinhibition, hyperexcitability, and abnormal synaptic plasticity.
authors.affiliation: 1 Institute of Neurophysiology, Charité - University Medicine Berlin, Berlin, Germany.|2 Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lippmann
authors.affiliation: 3 Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Lyn
authors.initials: L
authors.lastname: Kamintsky
authors.affiliation: 4 Helen Wills Neuroscience Institute and the Department of Integrative Biology, University of California, Berkeley, CA, USA.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: 3 Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lublinsky
authors.affiliation: 3 Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Prager
authors.affiliation: 1 Institute of Neurophysiology, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Julia Friederike
authors.initials: JF
authors.lastname: Nichtweiss
authors.affiliation: 1 Institute of Neurophysiology, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Seda
authors.initials: S
authors.lastname: Salar
authors.affiliation: 4 Helen Wills Neuroscience Institute and the Department of Integrative Biology, University of California, Berkeley, CA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaufer
authors.affiliation: 5 Neuroscience Research Center, Berlin, Germany.|6 Excellence Cluster NeuroCure, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
authors.affiliation: 3 Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|7 Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Canada.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020520:Brain Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D015536:Down-Regulation; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007427:Intracranial Pressure / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D009415:Nerve Net / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A
keywords: Blood–brain barrier; hippocampus; inhibition; seizures; synaptic plasticity