Article abstract
Nature Neuroscience 11, 940 - 948 (2008)
Published online: 20 July 2008 | doi:10.1038/nn.2142
PICK1 uncoupling from mGluR7a causes absence-like seizures
Federica Bertaso1,5, Chuansheng Zhang2,4,5, Astrid Scheschonka2, Frédéric de Bock1, Pierre Fontanaud1, Philippe Marin1, Richard L Huganir3, Heinrich Betz2, Joël Bockaert1, Laurent Fagni1 & Mireille Lerner-Natoli1
Abstract
Absence epilepsy is a neurological disorder that causes a recurrent loss of consciousness and generalized spike-and-wave discharges on an electroencephalogram (EEG). The role of metabotropic glutamate receptors (mGluRs) and associated scaffolding proteins in absence epilepsy has been unclear to date. We investigated a possible role for these proteins in absence epilepsy, focusing on the mGluR7a receptor and its PDZ-interacting protein, protein interacting with C kinase 1 (PICK1), in rats and mice. Injection of a cell-permeant dominant-negative peptide or targeted mutation of the mGluR7a C terminus, both of which disrupt the interaction between the receptor and PDZ proteins, caused behavioral symptoms and EEG discharges that are characteristic of absence epilepsy. Inactivation of the Pick1 gene also facilitated pharmacological induction of the absence epilepsy phenotype. The cortex and thalamus, which are known to participate in absence epilepsy, were involved, but the hippocampus was not. Our results indicate that disruption of the mGluR7a-PICK1 complex is sufficient to induce absence epilepsy–like seizures in rats and mice, thus providing, to the best of our knowledge, the first animal model of metabotropic glutamate receptor–PDZ protein interaction in absence epilepsy.
- CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France, INSERM, U661, Montpellier, France and Université Montpellier, 1, 2, 141 rue de la Cardonille, 34094 Montpellier, Cedex 5, France.
- Department of Neurochemistry, Max-Planck Institute for Brain Research, Hirnforschung Postfach 71 06 62, 60528 Frankfurt, Germany.
- Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 N. Wolfe St. Baltimore, Maryland 21205, USA.
- Present address: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
- These authors contributed equally to this work.
Correspondence to: Joël Bockaert1 e-mail: joel.bockaert@igf.cnrs.fr
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