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Transcriptional regulation of NRF1 on metabotropic glutamate receptors in a neonatal hypoxic‑ischemic encephalopathy rat model

Pediatric Research volume 93, pages 1865–1872 (2023)Cite this article

Abstract

Background

Neonatal hypoxic-ischemic encephalopathy (HIE) is a kind of brain injury that causes severe neurological disorders in newborns. Metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs) are significantly associated with HIE and are involved in ischemia-induced excitotoxicity. This study aimed to investigate the upstream mechanisms of mGluRs and the transcriptional regulation by nuclear respiratory factor 1 (NRF1).

Methods

The rat model of neonatal HIE was created using unilateral carotid artery ligation and in vitro oxygen-glucose deprivation paradigm. We used western blot, immunofluorescence, Nissl staining, and Morris water maze to investigate the impact of NRF1 on brain damage and learning memory deficit by HIE. We performed ChIP and luciferase activities to identify the transcriptional regulation of NRF1 on mGluRs.

Results

The neuronal NRF1 and some glutamatergic genes expression synchronously declined in infarcted tissues. The NRF1 overexpression effectively restored the expression of some glutamatergic genes and improved cognitive performance. NRF1 regulated some members of mGluRs and iGluRs in hypoxic-ischemic neurons. Finally, NRF1 is bound to the promoter regions of Grm1, Grm2, and Grm8 to activate their transcription.

Conclusions

NRF1 is involved in the pathology of the neonatal HIE rat model, suggesting a novel therapeutic approach to neonatal HIE.

Impact

  • NRF1 and some glutamatergic genes were synchronously downregulated in the infarcted brain of the neonatal HIE rat model.

  • NRF1 overexpression could rescue cognitive impairment caused by the neonatal HIE rat model.

  • NRF1 regulated the expressions of Grm1, Grm2, and Grm8, which activated their transcription by binding to the promoter regions.

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Fig. 1: The expression of NRF1 in ischemic brain tissue of neonatal HIE rats.
Fig. 2: Downregulation of glutamatergic candidate genes in neonatal HIE rats.
Fig. 3: The NRF1 overexpression improved cognitive function and restored the glutamatergic candidate gene expression in neonatal HIE rats.
Fig. 4: Upregulation of mGluRs in NRF1 OE neurons after OGD treatments.
Fig. 5: Transcriptional regulation of NRF1 on mGluRs in OGD neurons.

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Acknowledgements

We thank Xiaomei Wu from Nantong University, who kindly provided PC12 cells as gifts. We also thank Qianqian Luo and Yapeng Lu at Nantong University for their suggestions for experimental design.

Funding

The National Natural Science Foundation of China (31671206) and the Special Foundation for Excellent Young Teachers and Principals Program of Jiangsu Province supported the study.

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Authors and Affiliations

  1. Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China

    Dan Wang, Mengqing Xu, Linlin Huang, Xueting Wang & Li Zhu

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Contributions

L.Z. and D.W. conceived the study. D.W., M.Q.X., and L.L.H. performed the experiments, analyses, and interpreted the data. D.W. and X.T.W. drafted the article, and all authors contributed to the manuscript. L.Z. reviewed the manuscript and approved the final version.

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Correspondence to Li Zhu.

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Wang, D., Xu, M., Huang, L. et al. Transcriptional regulation of NRF1 on metabotropic glutamate receptors in a neonatal hypoxic‑ischemic encephalopathy rat model. Pediatr Res 93, 1865–1872 (2023). https://doi.org/10.1038/s41390-022-02353-9

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