RT Journal Article
SR Electronic
T1 Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 253310
DO 10.1101/253310
A1 Michael V. Lombardo
A1 Bonnie Auyeung
A1 Tiziano Pramparo
A1 Angélique Quartier
A1 Jérémie Courraud
A1 Rosemary J. Holt
A1 Jack Waldman
A1 Amber N. V. Ruigrok
A1 Natasha Mooney
A1 Meng-Chuan Lai
A1 Prantik Kundu
A1 Edward T. Bullmore
A1 Jean-Louis Mandel
A1 Amélie Piton
A1 Simon Baron-Cohen
YR 2018
UL http://biorxiv.org/content/early/2018/01/24/253310.abstract
AB Many early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sex-specific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.