Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II.
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.
Department of Psychiatry, Laboratory of Molecular and Psychiatric Neuroscience, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478, USA.
Liqun
L
Han
Jonathan D
JD
Picker
Laura R
LR
Schaevitz
Guochuan
G
Tsai
Jiamin
J
Feng
Zhichun
Z
Jiang
Hillary C
HC
Chu
Alo C
AC
Basu
Joanne
J
Berger-Sweeney
Joseph T
JT
Coyle
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005091:Exons / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D043425:Glutamate Carboxypeptidase II / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D007398:Interpersonal Relations; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D055139:Sensory Gating / Q000235:genetics; D013028:Space Perception / Q000502:physiology
D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D043425:Glutamate Carboxypeptidase II; C485064:Glutamate carboxypeptidase III, mouse