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Knock-in mice lacking the PDZ-ligand motif of mGluR7a show impaired PKC-dependent autoinhibition of glutamate release, spatial working memory deficits, and increased susceptibility to pentylenetetrazol.

The metabotropic glutamate receptor 7 (mGluR7) is widely expressed throughout the brain and primarily localized at presynaptic active zones, where it is thought to regulate neurotransmitter release. Protein interacting with C kinase 1 (PICK1), a postsynaptic density protein-95/disc-large tumor suppressor protein/zonula occludens-1 (PDZ)-domain protein, binds to the three C-terminal amino acids (-LVI) of the predominant mGluR7 splice variant, mGluR7a, and has been implicated in the synaptic clustering of this receptor. Here, we generated knock-in mice in which the C-terminal LVI coding sequence of exon 10 of the mGluR7 gene was replaced by three alanine codons (-AAA). Immunoprecipitation showed that the PICK1-mGluR7a interaction is disrupted in mGluR7a(AAA/AAA) mice. However, the synaptic localization of mGluR7a was not altered in cultured hippocampal neurons and brain sections prepared from the knock-in animals. In cerebellar granule cell cultures, the group III mGluR agonist l-AP-4 decreased the frequency of spontaneous excitatory currents in neurons derived from wild-type but not mGluR7a(AAA/AAA) mice, consistent with the interaction between mGluR7a and PICK1 being required for protein kinase C-mediated inhibition of glutamate release. At the behavioral level, the mGluR7a(AAA/AAA) mice showed no deficits in motor coordination, pain sensitivity, and anxiety but exhibited significant defects in hippocampus-dependent spatial working memory. In addition, they displayed a high susceptibility to the convulsant drug pentylenetetrazole. Together, these results indicate that PICK1 binding to the C-terminal region of mGluR7a is crucial for agonist-triggered presynaptic signaling in vivo.

Pubmed ID: 18716219


  • Zhang CS
  • Bertaso F
  • Eulenburg V
  • Lerner-Natoli M
  • Herin GA
  • Bauer L
  • Bockaert J
  • Fagni L
  • Betz H
  • Scheschonka A


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

August 20, 2008

Associated Grants


Mesh Terms

  • Amino Acid Motifs
  • Animals
  • Behavior, Animal
  • Brain
  • Carrier Proteins
  • Cells, Cultured
  • Cerebellum
  • Convulsants
  • Excitatory Amino Acid Antagonists
  • Genetic Predisposition to Disease
  • Glutamic Acid
  • Ligands
  • Memory Disorders
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neural Inhibition
  • Nuclear Proteins
  • Oocytes
  • Pentylenetetrazole
  • Presynaptic Terminals
  • Protein Isoforms
  • Protein Kinase C
  • Receptors, Metabotropic Glutamate
  • Seizures
  • Signal Transduction
  • Space Perception
  • Synapses
  • Xenopus laevis