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The Journal of Neuroscience, November 17, 2004, 24(46):10568-10578; doi:10.1523/JNEUROSCI.4579-03.2004

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Cellular/Molecular
A Genetic Switch for Epilepsy in Adult Mice

Heinz E. Krestel,¹ Derya R. Shimshek,¹ Vidar Jensen,³ Thomas Nevian,² Jinhyun Kim,¹ Yu Geng,¹ Thomas Bast,⁴ Antoine Depaulis,⁵ Kai Schonig,⁶ Frieder Schwenk,⁷ Hermann Bujard,⁶ Øivind Hvalby,³ Rolf Sprengel,¹ and Peter H. Seeburg¹

Departments of ¹Molecular Neurobiology and ²Cell Physiology, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany, ³Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway, ⁴Department of Pediatric Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany, ⁵Institut National de la Santé et de la Recherche Médicale, Unité 398, FacultédeMédicine, 67085 Strasbourg, France, ⁶Center for Molecular Biology Heidelberg, 69210 Heidelberg, Germany, and ⁷Artemis Pharmaceuticals and Exelixis, 51063 Cologne, Germany

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.

Key words: temporal Cre regulation; RNA editing; spinous calcium transients; altered AMPA receptors; hippocampus; population spike

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Received June 11, 2003; revised August 27, 2004; accepted September 30, 2004.

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