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.
Zhang
Chuan-Sheng
CS
Department of Neurochemistry, Max Planck Institute for Brain Research, 60528 Frankfurt am Main, Germany.
Bertaso
Federica
F
Eulenburg
Volker
V
Lerner-Natoli
Mireille
M
Herin
Greta Ann
GA
Bauer
Liane
L
Bockaert
Joel
J
Fagni
Laurent
L
Betz
Heinrich
H
Scheschonka
Astrid
A
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid; D008024:Ligands; D008569:Memory Disorders / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009433:Neural Inhibition; D009687:Nuclear Proteins / Q000378:metabolism*; D009865:Oocytes; D010433:Pentylenetetrazole; D017729:Presynaptic Terminals; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics*; D015398:Signal Transduction; D013028:Space Perception; D013569:Synapses; D014982:Xenopus laevis
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; D020033:Protein Isoforms; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D018698:Glutamic Acid; D011493:Protein Kinase C; D010433:Pentylenetetrazole