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PICK1 uncoupling from mGluR7a causes absence-like seizures

Nature Neuroscience volume 11, pages 940–948 (2008)Cite this article

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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Figure 1: In vitro validation of the uncoupling between mGluR7a and PICK1 by the TAT–R7-LVI peptide.
Figure 2: Brain diffusion and mGluR7-PICK1 dissociating effect of in vivo–administered TAT peptides.
Figure 3: Concomitant bilateral cortical discharges induced by disruption of the interaction between mGluR7a and PDZ domain proteins by TAT–R7-LVI in vivo.
Figure 4: Region-specific absence seizures induced by disruption of mGluR7a-PDZ ligand interactions.
Figure 5: Absence-like seizures induced by local injection of TAT–R7-LVI peptide in either cortex or thalamus in the rat.
Figure 6: Pharmacology of TAT–R7-LVI–induced absence-like discharges.
Figure 7: Spontaneous discharges recorded from the mGluR7aAAA/AAA mouse.
Figure 8: Absence-like seizures induced by disruption of PICK1-PDZ ligand interaction.

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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.).

Author information

Author notes

  1. Chuansheng Zhang

    Present address: Present address: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.,

  2. Federica Bertaso and Chuansheng Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France, INSERM, U661, Montpellier, France and Université Montpellier, 1, 2, 141 rue de la Cardonille, Montpellier, 34094, Cedex 5, France

    Federica Bertaso, Frédéric de Bock, Pierre Fontanaud, Philippe Marin, Joël Bockaert, Laurent Fagni & Mireille Lerner-Natoli

  2. Department of Neurochemistry, Max-Planck Institute for Brain Research, Hirnforschung Postfach 71 06 62, Frankfurt, 60528, Germany

    Chuansheng Zhang, Astrid Scheschonka & Heinrich Betz

  3. Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, 21205, Maryland, USA

    Richard L Huganir

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Contributions

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.

Corresponding author

Correspondence to Joël Bockaert.

Supplementary information

Supplementary Text and Figures

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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