Apnea of Prematurity induces short and long-term development-related transcriptional changes in the murine cerebellum

Current Research in Neurobiology

This paper aims to present transcriptomic data that participates in understanding the molecular basis for the histological and behavioral abnormalities caused by intermittent hypoxia.
Molecular Neurosciences
Neurodevelopment
Cerebellum
Apnea of Prematurity
RT-qPCR
Authors
Affiliations

Agalic Rodriguez-Duboc

Cancer and Brain Genomics

Magali Basille-Duguay

NorDic

Aurélien Debonne

Cancer and Brain Genomics

Marc-Aurèle Rivière

LITIS

David Vaudry

Cancer and Brain Genomics

Delphine Burel

Cancer and Brain Genomics

Published

October 20, 2023

Doi

10.1016/j.crneur.2023.100113

Abstract

Apnea of prematurity (AOP) occurs in over 50% of preterm infants and induces a perinatal intermittent hypoxia (IH) which represents a leading cause of morbimortality worldwide. At birth, the human cerebellar cortex is still immature, making it vulnerable to perinatal events. Moreover, a correlation between cerebellar functions and the deficits observed in children having suffered from AOP has been demonstrated. Yet, the cerebellar alterations underpinning this link remain poorly understood.

To shed light on the involvement of the cerebellum in perinatal hypoxia-related sequelae, we developed a mouse model of AOP. In previous works, we found that IH induces oxidative stress in the developing cerebellum as shown by the overexpression of genes involved in reactive oxygen species production, and the under-expression of genes encoding antioxidant enzymes. These alterations suggest a failure of the defense system against oxidative stress and could be responsible for neuronal death in the cerebellum.

Based on these results, we performed a transcriptomic study of the genes involved in the processes that occur during cerebellar development. We analyzed the expression of these genes at various developmental stages and in different cell types, by real time PCR. This enabled us to pinpoint a timeframe of vulnerability at P8, which represents the age with the highest number of downregulated genes in the cerebellum. Moreover, we identified several molecular pathways that are impacted by our IH protocol, such as proliferation, migration, and differentiation. This suggests that IH can modify the development of various cells, and then contribute to the histological and behavioral deficits already observed in this model.

Overall, our data indicate that the cerebellum is highly sensitive to IH, and provide elements to better understand the pathophysiology of AOP by deciphering its cellular and molecular causal mechanisms. In the long term, the present results could lead to the identification of novel therapeutic targets to improve the clinical management of this highly prevalent pathology.

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BibTeX citation:
@article{rodriguez-duboc2023,
  author = {Rodriguez-Duboc, Agalic and Basille-Duguay, Magali and
    Debonne, Aurélien and Rivière, Marc-Aurèle and Vaudry, David and
    Burel, Delphine},
  title = {Apnea of {Prematurity} Induces Short and Long-Term
    Development-Related Transcriptional Changes in the Murine
    Cerebellum},
  journal = {Current Research in Neurobiology},
  volume = {5},
  pages = {100113},
  date = {2023-10-20},
  url = {https://www.sciencedirect.com/science/article/pii/S2665945X23000414},
  doi = {10.1016/j.crneur.2023.100113},
  issn = {2665-945X},
  langid = {en},
  abstract = {Apnea of prematurity (AOP) occurs in over 50\% of preterm
    infants and induces a perinatal intermittent hypoxia (IH) which
    represents a leading cause of morbimortality worldwide. At birth,
    the human cerebellar cortex is still immature, making it vulnerable
    to perinatal events. Moreover, a correlation between cerebellar
    functions and the deficits observed in children having suffered from
    AOP has been demonstrated. Yet, the cerebellar alterations
    underpinning this link remain poorly understood. To shed light on
    the involvement of the cerebellum in perinatal hypoxia-related
    sequelae, we developed a mouse model of AOP. In previous works, we
    found that IH induces oxidative stress in the developing cerebellum
    as shown by the overexpression of genes involved in reactive oxygen
    species production, and the under-expression of genes encoding
    antioxidant enzymes. These alterations suggest a failure of the
    defense system against oxidative stress and could be responsible for
    neuronal death in the cerebellum. Based on these results, we
    performed a transcriptomic study of the genes involved in the
    processes that occur during cerebellar development. We analyzed the
    expression of these genes at various developmental stages and in
    different cell types, by real time PCR. This enabled us to pinpoint
    a timeframe of vulnerability at P8, which represents the age with
    the highest number of downregulated genes in the cerebellum.
    Moreover, we identified several molecular pathways that are impacted
    by our IH protocol, such as proliferation, migration, and
    differentiation. This suggests that IH can modify the development of
    various cells, and then contribute to the histological and
    behavioral deficits already observed in this model. Overall, our
    data indicate that the cerebellum is highly sensitive to IH, and
    provide elements to better understand the pathophysiology of AOP by
    deciphering its cellular and molecular causal mechanisms. In the
    long term, the present results could lead to the identification of
    novel therapeutic targets to improve the clinical management of this
    highly prevalent pathology.}
}
For attribution, please cite this work as:
Rodriguez-Duboc, A., Basille-Duguay, M., Debonne, A., Rivière, M.-A., Vaudry, D., & Burel, D. (2023). Apnea of Prematurity induces short and long-term development-related transcriptional changes in the murine cerebellum. Current Research in Neurobiology, 5, 100113. https://doi.org/10.1016/j.crneur.2023.100113