title: 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: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yang
authors: Y
authors: Gao
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Siyi
authors: S
authors: Xu
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Zhenwen
authors: Z
authors: Cui
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Mingkun
authors: M
authors: Zhang
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yingying
authors: Y
authors: Lin
authors: Shanghai Research Center for Model Organisms, Shanghai, China.
authors: Lei
authors: L
authors: Cai
authors: Shanghai Research Center for Model Organisms, Shanghai, China.
authors: Zhugang
authors: Z
authors: Wang
authors: Department of Psychiatry, Yale University School of Medicine, West Haven, Connecticut, USA.
authors: Xingguang
authors: X
authors: Luo
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yan
authors: Y
authors: Zheng
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yong
authors: Y
authors: Wang
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Qizhong
authors: Q
authors: Luo
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Jiyao
authors: J
authors: Jiang
authors: Department of Biology, Georgetown University, Washington, DC, USA.
authors: Joseph H
authors: JH
authors: Neale
authors: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Chunlong
authors: C
authors: Zhong
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001930:Brain Injuries / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D043425:Glutamate Carboxypeptidase II / Q000172:deficiency*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D043425:Glutamate Carboxypeptidase II
keywords: Glutamate carboxypep-tidase II; N-acetylaspartylglutamate; behavior; gene knockout; histopathology; traumatic brain injury