Premium
Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II
Author(s) -
Han Liqun,
Picker Jonathan D.,
Schaevitz Laura R.,
Tsai Guochuan,
Feng Jiamin,
Jiang Zhichun,
Chu Hillary C.,
Basu Alo C.,
BergerSweeney Joanne,
Coyle Joseph T.
Publication year - 2009
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20649
Subject(s) - glutamate receptor , nmda receptor , glutamate carboxypeptidase ii , biology , metabotropic glutamate receptor , endocrinology , medicine , agonist , metabotropic glutamate receptor 3 , receptor , microbiology and biotechnology , biochemistry , genetics , prostate , cancer
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbed glutamate signaling resulting in hypofunction of N ‐methyl‐ D ‐aspartate receptors (NMDAR) has been implicated in the pathophysiology of schizophrenia. Glutamate Carboxypeptidase II (GCP II) hydrolyzes N ‐acetyl‐alpha L ‐aspartyl‐ L ‐glutamate (NAAG) into glutamate and N ‐acetyl‐aspartate. NAAG is a neuropeptide that is an NMDAR antagonist as well as an agonist for the metabotropic glutamate receptor‐3 (mGluR3), which inhibits glutamate release. The aggregate effect of NAAG is thus to attenuate NMDAR activation. To manipulate the expression of GCP II, LoxP sites were inserted flanking exons 1 and 2, which were excised by crossing with a Cre‐expressing mouse. The mice heterozygous for this deletion showed a 50% reduction in the expression level of protein and functional activity of GCP II in brain samples. Heterozygous mutant crosses did not yield any homozygous null animals at birth or as embryos ( N > 200 live births and fetuses). These data are consistent with the previous report that GCP II homozygous mutant mice generated by removing exons 9 and 10 of GCP II gene were embryonically lethal and confirm our hypothesis that GCP II plays an essential role early in embryonic development. Heterozygous mice, however, developed normally to adulthood and exhibited increased locomotor activity, reduced social interaction, and a subtle cognitive deficit in working memory. Synapse 63:625–635, 2009. © 2009 Wiley‐Liss, Inc.