PICK1 uncoupling from mGluR7a causes absence-like seizures

Nat Neurosci. 2008 Aug;11(8):940-8. doi: 10.1038/nn.2142. Epub 2008 Jul 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins
  • Cells, Cultured
  • Disease Models, Animal*
  • Electrodes, Implanted
  • Electroencephalography / drug effects
  • Epilepsy, Absence / genetics
  • Epilepsy, Absence / metabolism
  • Epilepsy, Absence / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides / pharmacology
  • Phenotype
  • Protein Binding / drug effects
  • Protein Structure, Tertiary / drug effects
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology


  • Carrier Proteins
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Peptides
  • Prkcabp protein, mouse
  • Protein Subunits
  • Receptors, Metabotropic Glutamate
  • Recombinant Fusion Proteins
  • TAT-R7-LV1 peptide
  • metabotropic glutamate receptor 7