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MNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury.

ABSTRACT: N-acetyl aspartyl-glutamate (NAAG) is easily inactivated for the hydrolysis of NAAG peptidase on the surface of glial cells, thereby losing its endogenous neuroprotective effect after traumatic brain injury. In this study, lentiviral vectors were used to over express/knock out NAAG synthetase II (Rimkla) in mouse embryonic neural stem cells (mNSCs) in vitro and these mNSCs were transplanted at the lesion site in a mouse model of controlled cortical impact (CCI). In vivo experiments showed that transplantation of mNSCs overexpressing Rimkla regulated glutamate-glutamine cycling between adjacent astrocytes and neurons in the subacute phase of CCI, thereby enhancing support for neuronal metabolism and promoting neuronal synaptic repair in the hippocampal CA3 region. Taken together, these findings demonstrate that transplantation of neural stem cells overexpressing Rimkla can effectively increase the NAAG concentration in local brain regions, which opens up new ideas for the maintenance of NAAG neuroprotective effects after TBI.

SUBMITTER: Ji T

PROVIDER: S-EPMC10550729 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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mNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury.

Ji Tongjie T Pang Ying Y Cheng Meng M Wang Rui R Chen Xu X Zhang Chunyu C Liu Min M Zhang Jing J Zhong Chunlong C

iScience 20230914 10

N-acetyl aspartyl-glutamate (NAAG) is easily inactivated for the hydrolysis of NAAG peptidase on the surface of glial cells, thereby losing its endogenous neuroprotective effect after traumatic brain injury. In this study, lentiviral vectors were used to over express/knock out NAAG synthetase II (Rimkla) in mouse embryonic neural stem cells (mNSCs) in vitro and these mNSCs were transplanted at the lesion site in a mouse model of controlled cortical impact (CCI). In vivo expe ...[more]

PMID: 37810220

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Project description:Functional outcome following traumatic brain injury (TBI) varies greatly, with approximately half of those who survive suffering long-term motor and cognitive deficits despite contemporary rehabilitation efforts. We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) enhances rehabilitation of motor deficits that result from brain injury. The objective of the present study was to evaluate the efficacy of LCN DBS on recovery from rodent TBI that uniquely models the injury location, chronicity and resultant cognitive symptoms observed in most human TBI patients. We used controlled cortical impact (CCI) to produce an injury that targeted the medial prefrontal cortex (mPFC-CCI) bilaterally, resulting in cognitive deficits. Unilateral LCN DBS electrode implantation was performed 6 weeks post-injury. Electrical stimulation started at week eight post-injury and continued for an additional 4 weeks. Cognition was evaluated using baited Y-maze, novel object recognition task and Barnes maze. Post-mortem analyses, including Western Blot and immunohistochemistry, were conducted to elucidate the cellular and molecular mechanisms of recovery. We found that mPFC-CCI produced significant cognitive deficits compared to pre-injury and naïve animals. Moreover, LCN DBS treatment significantly enhanced the long-term memory process and executive functions of applying strategy. Analyses of post-mortem tissues showed significantly greater expression of CaMKIIα, BDNF and p75NTR across perilesional cortex and higher expression of postsynaptic formations in LCN DBS-treated animals compared to untreated. Overall, these data suggest that LCN DBS is an effective treatment of cognitive deficits that result from TBI, possibly by activation of ascending, glutamatergic projections to thalamus and subsequent upregulation of thalamocortical activity that engages neuroplastic mechanisms for facilitation of functional re-organization. These results support a role for cerebellar output neuromodulation as a novel therapeutic approach to enhance rehabilitation for patients with chronic, post-TBI cognitive deficits that are unresponsive to traditional rehabilitative efforts.

Dataset Information

MNSCs overexpressing Rimkla transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury.

Publications

mNSCs overexpressing <i>Rimkla</i> transplantation facilitates cognitive recovery in a mouse model of traumatic brain injury.

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