Mice lacking glutamate carboxypeptidase II develop normally, but are less susceptible to traumatic brain injury.

Abstract

Glutamate carboxypeptidase II (GCPII) is a transmembrane zinc metallopeptidase found mainly in the nervous system, prostate and small intestine. In the nervous system, glia-bound GCPII mediates the hydrolysis of the neurotransmitter N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate. Inhibition of GCPII has been shown to attenuate excitotoxicity associated with enhanced glutamate transmission under pathological conditions. However, different strains of mice lacking the GCPII gene are reported to exhibit striking phenotypic differences. In this study, a GCPII gene knockout (KO) strategy involved removing exons 3-5 of GCPII. This generated a new GCPII KO mice line with no overt differences in standard neurological behavior compared to their wild-type (WT) littermates. However, GCPII KO mice were significantly less susceptible to moderate traumatic brain injury (TBI). GCPII gene KO significantly lessened neuronal degeneration and astrocyte damage in the CA2 and CA3 regions of the hippocampus 24 h after moderate TBI. In addition, GCPII gene KO reduced TBI-induced deficits in long-term spatial learning/memory tested in the Morris water maze and motor balance tested via beam walking. Knockout of the GCPII gene is not embryonic lethal and affords histopathological protection with improved long-term behavioral outcomes after TBI, a result that further validates GCPII as a target for drug development consistent with results from studies using GCPII peptidase inhibitors.

• Authors: Yang Gao, Siyi Xu, Zhenwen Cui, Mingkun Zhang, Yingying Lin, Lei Cai, Zhugang Wang, Xingguang Luo, Yan Zheng, Yong Wang, Qizhong Luo, Jiyao Jiang, Joseph H Neale, Chunlong Zhong
• Journal: Journal of neurochemistry (J Neurochem) Vol. 134 Issue 2 Pg. 340-53 (Jul 2015) ISSN: 1471-4159 [Electronic] England
• PMID: 25872793 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 International Society for Neurochemistry.

Chemical References

• Glutamate Carboxypeptidase II

Topics

• Animals
• Behavior, Animal (physiology)
• Brain Injuries (enzymology, genetics, pathology)
• Disease Models, Animal
• Glutamate Carboxypeptidase II (deficiency)
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout