Astrocyte-derived thrombospondin induces cortical synaptogenesis in a sex-specific manner.

Abstract

The regulation of synaptic connectivity in the brain is vital to proper functioning and development of the central nervous system (CNS). Formation of neural networks in the CNS has been shown to be heavily influenced by astrocytes, which secrete factors, including thrombospondin (TSP) family proteins, that promote synaptogenesis. However, whether this process is different between males and females has not been thoroughly investigated. In this study, we found that cortical neurons purified from newborn male rats showed a significantly more robust synaptogenic response compared to female-derived cells when exposed to factors secreted from astrocytes. This difference was driven largely by the neuronal response to TSP2, which increased synapses in male neurons while showing no effect on female neurons. Blockade of endogenous 17{beta}-estradiol production with letrozole normalized the TSP response between male and female cells, indicating a level of regulation by estrogen signaling. Our results suggest that TSP-induced synaptogenesis is critical for the development of male but not female cortical synapses, contributing to sex differences in astrocyte-mediated synaptic connectivity.