title: A genetic switch for epilepsy in adult mice.
abstract: Premature death from seizures afflicts gene-targeted mice expressing the Q/R site-unedited glutamate receptor subunit GluR-B(Q) of AMPA receptors in central neurons. Early seizure-related death has now been circumvented by a genetic switch that restricts GluR-B(Q) expression to forebrain principal neurons from postnatal stages onward, prominently in hippocampus and striatum and less so in cortex and amygdala. When switched on, functional receptor incorporation of GluR-B(Q) could be demonstrated by imaging evoked AMPA channel-mediated spinous Ca2+ transients in CA1 pyramidal cells. Sustained GluR-B(Q) expression in adult mice led to smaller excitatory postsynaptic responses in the CA1 region with unchanged presynaptic fiber excitability. Notably, despite the smaller excitatory response, the CA1 cells exhibited a reduced population spike threshold, which might underlie the spontaneous manifestations of epilepsy, including myocloni and generalized seizures with limbic components, observed by synchronous video monitoring and electroencephalographic recordings. No neuropathological symptoms developed when GluR-B(Q) expression was restricted to only hippocampal neurons. Our results show that seizure susceptibility is triggered by GluR-B(Q) expression also in the adult brain and that circuit hyperexcitability is not an immediate consequence of GluR-B(Q) but requires yet unknown downstream events, likely to be induced by non-Hebbian plasticity from Ca2+-permeable AMPA channels in principal neurons.
authors.affiliation: Department of Molecular Neurobiology, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany.
authors.forename: Heinz E
authors.initials: HE
authors.lastname: Krestel
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.forename: Vidar
authors.initials: V
authors.lastname: Jensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Nevian
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Kim
authors.forename: Yu
authors.initials: Y
authors.lastname: Geng
authors.forename: Thomas
authors.initials: T
authors.lastname: Bast
authors.forename: Antoine
authors.initials: A
authors.lastname: Depaulis
authors.forename: Kai
authors.initials: K
authors.lastname: Schonig
authors.forename: Frieder
authors.initials: F
authors.lastname: Schwenk
authors.forename: Hermann
authors.initials: H
authors.lastname: Bujard
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Hvalby
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000502:physiology; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000254:growth & development / Q000503:physiopathology; D019426:Integrases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010641:Phenotype; D016548:Prosencephalon / Q000254:growth & development / Q000378:metabolism; D017966:Pyramidal Cells / Q000502:physiology; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics*; D009435:Synaptic Transmission; D019076:Transgenes
chemical_list: D018091:Receptors, AMPA; C115953:glutamate receptor type B; C045073:Cre recombinase; D019426:Integrases; D002118:Calcium