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The Journal of Neuroscience, August 20, 2008, 28(34):8604-8614; doi:10.1523/JNEUROSCI.0628-08.2008

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Cellular/Molecular
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

Chuan-Sheng Zhang,^1 * Federica Bertaso,^2 * Volker Eulenburg,^1 * Mireille Lerner-Natoli,² Greta Ann Herin,¹ Liane Bauer,¹ Joel Bockaert,² Laurent Fagni,² Heinrich Betz,¹ and Astrid Scheschonka¹

¹Department of Neurochemistry, Max Planck Institute for Brain Research, 60528 Frankfurt am Main, Germany, and ²Institut de Génomique Fouctionelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, INSERM U-661, University of Montpellier I and II, 34094 Montpellier Cedex 05, France

Correspondence should be addressed to Dr. Heinrich Betz, Department of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany. Email: neurochemie{at}mpih-frankfurt.mpg.de

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.

Key words: metabotropic glutamate receptor 7; PICK1; synaptic clustering; PKC signaling; working memory; pentylenetetrazol

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Received Feb. 12, 2008; revised July 2, 2008; accepted July 12, 2008.

Correspondence should be addressed to Dr. Heinrich Betz, Department of Neurochemistry, Max Planck Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany. Email: neurochemie{at}mpih-frankfurt.mpg.de

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