ESPE Abstracts

Background: The pathophysiological link between the stress axis and mental health disorders is well established. However, the impact of inborn errors of steroidogenesis on the brain remains elusive. We analysed the brain transcriptome of adult zebrafish with impaired steroidogenesis to study the role of steroid hormones in the development of mental and psychiatric disorders.

Methods: Adult brains from two established zebrafish lines with differentially impaired steroidogenesis, 21-hydroxylase deficiency (cyp21a2-/-) and side-chain cleavage enzyme deficiency (cyp11a2-/-), were used. We analysed 18 months old male and female wildtypes and cyp21a2-/- mutants (6 in each group), and 4 wildtype and 5 cyp11a2-/- mutant males (no female mutant progeny as part of the mutant phenotype) that were 12 months old. Following RNA extraction and paired-end sequencing, transcriptomic analysis included differential gene expression (DGE) analysis, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and enrichment analysis of disease-associated genes.

Results: For both mutant lines, the most significantly differentially expressed genes were downregulated, including glucocorticoid-response genes klf9 and fkbp5, as well as chaperone-mediated protein folding heat shock protein hsp90aa1.2, and nfkbiab involved in the regulation of CNS development. In cyp21a2-/- fish, enrichment GO analysis showed dysregulation of chaperone-mediated protein folding and organic acid transport in males, and response to hypoxia in females. Meanwhile, in cyp11a2-/- mutants, multiple dysregulations were found for biological processes involved in immune response, provision of energy precursors, and circadian rhythm. For both cyp21a2-/- and cyp11a2-/- males, GSEA revealed downregulation of processes involved in synapse organization and signalling, as well as metabolic processes involved in energy homeostasis. Upregulation was observed for ribosome biogenesis and inflammatory response. In contrast, in female cyp21a2-/- fish, the majority of dysregulated biological processes were related to cell division and reproduction. The analysis of the association with human disease identified similar neurological conditions between all mutant groups, including Alzheimer’s disease, dementia, cognitive impairment, depressive and mood disorders, and autistic spectrum disorder.

Conclusion: These findings indicate that impaired steroidogenesis affects multiple processes involved in the functioning of the adult zebrafish brain. Synapse signalling and cell energy homeostasis processes are repressed, while inflammatory responses are upregulated. Such dysregulations may impact the pathogenesis of human mental conditions such as dementia and mood disorders. These effects appear to be influenced by sex, suggesting that sex hormones may have important roles in the pathogenesis of mental health disease. Further in-depth research using models of differentially impaired steroidogenesis and altered signalling is warranted.