Summary: Thrombospondin-2, a protein with cell adhesion properties usually secreted by astrocytes, prompted a strong increase in synapses in male-derived neurons but showed no effect in females.
Source: Marshall University
During development, brain cells may find different ways to connect with each other based on sex, according to researchers at the Marshall University Joan C. Edwards School of Medicine.
The study, recently published in eNeuro, showed a significantly more robust synaptogenic response in male-derived cells compared to female-derived cells when exposed to factors secreted from astrocytes, which are non-neuronal cells found throughout the central nervous system.
This difference was driven largely by how neurons responded to thrombospondin-2 (TSP2), a protein with cell adhesion properties that is normally secreted by astrocytes. In the study, TSP2 prompted a strong increase in synapses in male neurons while showing no effect on female neurons.
This work provides strong evidence that synapses, which serve as the basic building blocks for brain connectivity, may be formed by vastly different mechanisms during early development.
“Our goal is to better understand at a basic cellular level if there are sex differences in how cellular networks form in the brain,” said W. Christopher Risher, Ph.D., an assistant professor of biomedical sciences at the Joan C. Edwards School of Medicine and corresponding author on the study.
“In this study, for the first time, we see evidence that events which were always assumed to be occurring in the same manner, regardless of sex, may actually be completely different in males compared to females. The fact that these differences involve astrocytes, which have traditionally been ignored in neuroscience but have recently become a hot topic for study, makes them all the more intriguing.”
Risher’s team, led by first author Anna Mazur, Ph.D., isolated brain cells (neurons and astrocytes) from male and female newborn rats for this study. Once the cells were isolated, they were cultured for up to two weeks in various combinations with each other and then imaged on a fluorescent microscope to determine how many synapses were formed at the end of the experiment.
In addition, the cells were treated with TSP2 as well as numerous regulators of estrogen signaling, in order to determine the effect of each of these factors on synapse formation in male- and female-derived cultures.
“The fact that we have identified molecular pathways present in males that are either absent or less prominent in females indicates that there may be much that researchers have missed in the area of synaptic development, simply because we weren’t looking separately at males and females,” Risher said.
Risher and his team continue to research the presence and impact of differences in cellular networks. Ultimately, findings from their work could help pave the way for sex-specific therapies for neurodevelopmental disorders, such as autism spectrum disorder and schizophrenia, that present with strong sex biases in humans.
About this neurodevelopment research news
Source: Marshall University
Contact: Sheanna Spence – Marshall University
Image: The image is credited to W. Christopher Risher, Ph.D. Marshall University
Original Research: Closed access.
“Astrocyte-derived thrombospondin induces cortical synaptogenesis in a sex-specific manner” by Anna Mazur, Ean H. Bills, Kayla M. DeSchepper, James C. Williamson, Brandon J. Henderson and W. Christopher Risher. eNeuro
Abstract
Astrocyte-derived thrombospondin induces cortical synaptogenesis in a sex-specific manner
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 thrombospondin-2 (TSP2), which increased synapses in male neurons while showing no effect on female neurons. Blockade of endogenous 17β-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 male and female neurons show a divergent response to TSP synaptogenic signaling, contributing to sex differences in astrocyte-mediated synaptic connectivity.
Significance Statement
The regulation of synaptic connectivity by astrocytes has been a focus of both the neurodevelopmental and glial biology fields for nearly two decades, but many key findings did not take into account the possibility of sex differences.
For the first time, we show that a prominent astrocyte signaling factor, thrombospondin-2, strongly promotes synapse formation in male but not female neurons. Furthermore, this sex difference can be abolished by inhibiting production of 17β-estradiol, revealing that this astrocyte synaptogenic pathway is regulated by estrogen.
Our findings should prompt serious consideration into the ramifications of sex and sex hormones on astrocyte synaptic signaling as well as encourage and inform future studies, including potential implications for neurodevelopmental disorders that present with strong sex biases.
