TY - JOUR
T1 - PICK1 uncoupling from mGluR7a causes absence-like seizures
AU - Bertaso, Federica
AU - Zhang, Chuansheng
AU - Scheschonka, Astrid
AU - De Bock, Frédéric
AU - Fontanaud, Pierre
AU - Marin, Philippe
AU - Huganir, Richard L.
AU - Betz, Heinrich
AU - Bockaert, Joël
AU - Fagni, Laurent
AU - Lerner-Natoli, Mireille
N1 - Funding Information:
We thank A. Cohen-Solal for animal handling, M.-C. Rousset and M. Gien-Asari for assistance with immunohistochemistry and movie preparation, and A. Depaulis, B. Chanrion and C. Sharpe for helpful discussion. This work was supported by the Agence Nationale de la Recherche (ANR-05-NEURO-035 and ANR-06-NEURO-035), the Max-Planck-Gesellschaft, European Community (QLG3-CT-2001-00929), the Fonds der Chemischen Industrie and Ligue Franc¸aise Contre l’Epilepsie (F.B.).
PY - 2008/8
Y1 - 2008/8
N2 - 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.
AB - 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.
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U2 - 10.1038/nn.2142
DO - 10.1038/nn.2142
M3 - Article
C2 - 18641645
AN - SCOPUS:48149087060
SN - 1097-6256
VL - 11
SP - 940
EP - 948
JO - Nature neuroscience
JF - Nature neuroscience
IS - 8
ER -