title: PICK1 uncoupling from mGluR7a causes absence-like seizures.
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.
authors.affiliation: CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France, INSERM, U661, Montpellier, France and Université Montpellier, 1, 2, 141 rue de Cardonille, 34094 Montpellier, Cedex 5, France.
authors.forename: Federica
authors.initials: F
authors.lastname: Bertaso
authors.forename: Chuansheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Astrid
authors.initials: A
authors.lastname: Scheschonka
authors.forename: Frédéric
authors.initials: F
authors.lastname: de Bock
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontanaud
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Heinrich
authors.initials: H
authors.lastname: Betz
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Laurent
authors.initials: L
authors.lastname: Fagni
authors.forename: Mireille
authors.initials: M
authors.lastname: Lerner-Natoli
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010455:Peptides; C091822:Prkcabp protein, mouse; D021122:Protein Subunits; D018094:Receptors, Metabotropic Glutamate; D011993:Recombinant Fusion Proteins; C531467:TAT-R7-LV1 peptide; C102719:metabotropic glutamate receptor 7