PT  - JOURNAL ARTICLE
AU  - Chuan-Sheng Zhang
AU  - Federica Bertaso
AU  - Volker Eulenburg
AU  - Mireille Lerner-Natoli
AU  - Greta Ann Herin
AU  - Liane Bauer
AU  - Joel Bockaert
AU  - Laurent Fagni
AU  - Heinrich Betz
AU  - Astrid Scheschonka
TI  - 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
AID  - 10.1523/JNEUROSCI.0628-08.2008
DP  - 2008 Aug 20
TA  - The Journal of Neuroscience
PG  - 8604--8614
VI  - 28
IP  - 34
4099  - http://www.jneurosci.org/content/28/34/8604.short
4100  - http://www.jneurosci.org/content/28/34/8604.full
SO  - J. Neurosci.2008 Aug 20; 28
AB  - 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 mGluR7aAAA/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 mGluR7aAAA/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 mGluR7aAAA/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.