Sex Differences in Astroglial Cells in Telencephalic Development and Plasticity

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Sex differences exist from neuroanatomy to behaviour. As such, characterising sex differences in the building of neural systems over development is essential to understanding the contributions of sex to systems level neuroscience in adult brain functions. A great deal of research has identified astroglial cells as critical players in all central nervous system functions, including in the development and maintenance of neurons and neuronal networks. Given the involvement of astroglial cells in neuronal network function, it is perhaps not surprising that astroglial cells also show sex differences in morphology, gene/protein expression patterns and functions. Indeed, astroglial cells express sex hormone receptors and show rapid responses to hormonal manipulations, however few studies have examined sex differences in astroglial cells in telencephalic development. We recently used translating ribosome affinity purification together with RNA sequencing (TRAPseq) to phenotype the entire astroglial translatome in males and females at key developmental time points and in adulthood. Overall, we found two distinct astroglial phenotypes between early and late development, independent of sex. However, the astroglial translatome also showed marked sex differences in gene expression patterns over development, many of which were generally related to synapses and synaptic formation. Peak sex differences occurred during the second postnatal week, with males appearing to reach the mature astroglial phenotype earlier than females. The mechanism which induces these sex differences remains unknown, although one might hypothesize that these sex differences would be related to circulating sex hormone levels. However, the second postnatal week marks a unique time in development where sex hormones are largely dormant, suggesting that our findings are likely not reflective of in situ hormone levels. Instead, we hypothesize that sex differences in astroglial gene expression patterns are more likely part of a developmental program induced by perinatal exposure to hormones involved in sexual differentiation and/or directly induced by sex-linked chromosomes. In Aim 1, we will investigate the contribution of sex chromosomes and/or the perinatal sex hormones to the sex-specific astroglial gene expression patterns we observed and our finding that males reach the "mature" or "late" phenotype earlier. In Aim 2, we will focus our studies to examine the functional outcome of one of the sex differences suggested by our dataset, specifically the astroglial induction of neuronal synapses by estradiol. To achieve this, we will employ a range of tools and techniques including transgenic models and TRAPseq. The findings generated by the proposed studies will contribute to our understanding of general patterns in cortical development, sex differences in development and, finally to continue to elucidate astroglial contributions to neuronal network development and function.