title: Reactive astrogliosis causes the development of spontaneous seizures.
abstract: Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of β1-integrin (Itgβ1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted β1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl(-) gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35209, srobel@uab.edu.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Robel
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35209.
authors.forename: Susan C
authors.identifier: http://orcid.org/0000-0003-2483-3544
authors.initials: SC
authors.lastname: Buckingham
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35209.
authors.forename: Jessica L
authors.identifier: http://orcid.org/0000-0003-1219-3682
authors.initials: JL
authors.lastname: Boni
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35209.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Campbell
authors.affiliation: Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway, and.
authors.forename: Niels C
authors.initials: NC
authors.lastname: Danbolt
authors.affiliation: Institute of Physiology, Department of Physiological Genomics, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
authors.forename: Therese
authors.initials: T
authors.lastname: Riedemann
authors.affiliation: Institute of Physiology, Department of Physiological Genomics, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Sutor
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35209.
authors.forename: Harald
authors.initials: H
authors.lastname: Sontheimer
mesh_terms: D000200:Action Potentials; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D005911:Gliosis / Q000378:metabolism* / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D012640:Seizures / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D018698:Glutamic Acid; D019012:Integrin beta1; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse
keywords: EEG; astrocytes; astrogliosis; bumetanide; epilepsy; seizures