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.
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Acknowledgements
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 Française Contre l'Epilepsie (F.B.).
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F.B. and M.L.-N. conducted the experiments, F.d.B. and P.F. handled the softwares for data analyses, J.B. and L.F. supervised the project, P.M. contributed to the design of the TAT peptides, C.Z., A.S. and H.B. generated the mGluR7AAA/AAA mouse and R.L.H. generated the Pick1−/− mouse. F.B., M.L.-N., J.B., L.F., C.Z., A.S. and H.B. wrote the manuscript.
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Supplementary Figures 1–7 and Supplementary Methods (PDF 1536 kb)
Supplementary Movie 1
Movie and simultaneous EEG recording obtained 30 min after injection with 1 μmol TAT–R7-LVI (front rat) or TAT–R7-AAA (back rat). Note locomotor arrest and facial myoclonus in the front rat, as compared with normal exploratory activity of the control rat. (MOV 1135 kb)
Supplementary Movie 2
Movie and simultaneous EEG recording of absence-like behavior of an mGluR7aAAA/AAA mouse. Note a similar facial myoclonus and locomotor arrest as in TAT–R7-LVI–injected rat of Movie 1. (MOV 958 kb)
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Bertaso, F., Zhang, C., Scheschonka, A. et al. PICK1 uncoupling from mGluR7a causes absence-like seizures. Nat Neurosci 11, 940–948 (2008). https://doi.org/10.1038/nn.2142
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DOI: https://doi.org/10.1038/nn.2142
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