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Cerebellar Changes in Guinea Pig Offspring Following Suppression of Neurosteroid Synthesis During Late Gestation

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Abstract

Elevated gestational concentrations of allopregnanolone are essential for the development and neuroprotection of the foetal brain. Preterm birth deprives the foetus of these high levels of allopregnanolone, which may contribute to the associated adverse effects on cerebellar development. Preterm birth alters expression of GABAA receptor subunit composition, which may further limit neurosteroid action. The objective of this study was to determine the effects of suppression of allopregnanolone levels on the markers of development and functional outcome. Pregnant guinea pigs were treated with finasteride at a dose (25 mg/kg maternal weight) shown to suppress allopregnanolone between 60 days of gestation until delivery (term ∼71 days). The cerebella from neonates, whose mothers were treated with finasteride or vehicle during pregnancy, were collected at postnatal age 8. Pups that received finasteride displayed significantly greater glial fibrillary acid protein area coverage and reduced GABAA receptor α6-subunit messenger RNA within the cerebellum than pups that were exposed to vehicle. These findings indicate that loss of neurosteroid action on the foetal brain in late gestation produces prolonged astrocyte activation and reductions in GABAA receptor α6-subunit expression. These changes may contribute to the long-term changes in function associated with preterm birth.

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Acknowledgments

We acknowledge Dr. Greer Bennett for her contribution to the animal studies and Britt Saxby for her technical support and conducting the radioimmunoassays.

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Authors and Affiliations

  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 2308, New South Wales, Australia

    Angela L. Cumberland, Hannah K. Palliser & Jonathan J. Hirst

  2. Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, 2305, New South Wales, Australia

    Angela L. Cumberland, Hannah K. Palliser & Jonathan J. Hirst

  3. Hudson Institute of Medical Research, Clayton, 3168, Victoria, Australia

    David W. Walker

Authors
  1. Angela L. Cumberland
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Correspondence to Angela L. Cumberland.

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Funding

This study was funded by the National Health and Medical Research Council (grant number 10.83208).

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The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the National Health and Scientific Research Council Australian Code of Practice for the Care and Use of Animals for Scientific Purposes and had been approved by the University of Newcastle Animal Care and Ethics Committee. This article does not contain any studies with human participants performed by any of the authors.

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Cumberland, A.L., Palliser, H.K., Walker, D.W. et al. Cerebellar Changes in Guinea Pig Offspring Following Suppression of Neurosteroid Synthesis During Late Gestation. Cerebellum 16, 306–313 (2017). https://doi.org/10.1007/s12311-016-0802-0

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