Deletion of glutamate carboxypeptidase II (GCPII), but not GCPIII, provided long‐term benefits in mice with traumatic brain injury

Author:

Ji Tongjie1,Pang Ying1,Cheng Meng1,Wang Rui1,Chen Xu1,Zhang Chunyu1,Liu Min1,Zhang Jing12,Zhong Chunlong1ORCID

Affiliation:

1. Department of Neurosurgery Shanghai East Hospital, School of Medicine, Tongji University Shanghai China

2. Institute for Advanced Study Tongji University Shanghai China

Abstract

AbstractMain ProblemN‐acetylaspartylglutamate (NAAG) has neuroprotective effects in traumatic brain injury (TBI) by activating metabotropic glutamate receptor 3 (mGluR3) and reducing glutamate release. Glutamate carboxypeptidase II (GCPII) is the primary enzyme responsible for the hydrolysis of NAAG. It remains unclear whether glutamate carboxypeptidase III (GCPIII), a homolog of GCPII, can partially compensate for GCPII's function.MethodsGCPII−/−, GCPIII−/−, and GCPII/III−/− mice were generated using CRISPR/Cas9 technology. Mice brain injury model was established through moderate controlled cortical impact (CCI). The relationship between GCPII and GCPIII was explored by analyzing injury response signals in the hippocampus and cortex of mice with different genotypes at the acute (1 day) and subacute (7 day) phase after TBI.ResultsIn this study, we found that deletion of GCPII reduced glutamate production, excitotoxicity, and neuronal damage and improved cognitive function, but GCPIII deletion had no significant neuroprotective effect. Additionally, there was no significant difference in the neuroprotective effect between the combination of GCPII and GCPIII deletion and GCPII deletion alone.ConclusionThese results suggest that GCPII inhibition may be a therapeutic option for TBI, and that GCPIII may not act as a complementary enzyme to GCPII in this context.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Shanghai

Shanghai Pudong New Area Health Commission

Publisher

Wiley

Subject

Pharmacology (medical),Physiology (medical),Psychiatry and Mental health,Pharmacology

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