Abstract
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that is four times more commonly diagnosed in males than females. While susceptibility genes located in the sex chromosomes have been identified in ASD, it is unclear whether they are sufficient to explain the male bias or whether gonadal hormones also play a key role. We evaluated the sex chromosomal and hormonal influences on the male bias in a murine model of ASD, in which mice are exposed in utero to a maternal antibody reactive to contactin-associated protein-like 2 (Caspr2), which was originally cloned from a mother of a child with ASD (termed C6 mice henceforth). In this model, only male mice are affected. We used the four-core-genotypes (FCG) model in which the Sry gene is deleted from the Y chromosome (Y−) and inserted into autosome 3 (TgSry). Thus, by combining the C6 and FCG models, we were able to differentiate the contributions of sex chromosomes and gonadal hormones to the development of fetal brain and adult behavioral phenotypes. We show that the presence of the Y chromosome, or lack of two X chromosomes, irrespective of gonadal sex, increased the susceptibility to C6-induced phenotypes including the abnormal growth of the developing fetal cerebral cortex, as well as a behavioral pattern of decreased open-field exploration in adult mice. Our results indicate that sex chromosomes are the main determinant of the male bias in the maternal C6-induced model of ASD. The less dominant hormonal effect may be due to modulation by sex chromosome genes of factors involved in gonadal hormone pathways in the brain.
Highlights
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that manifest early in childhood
We measured the cortical plate (CP)/cortical zones’ (CZ) ratio (Figure 2A) in hormonal and chromosomal males and females exposed to C6 or B1, as we had shown this ratio to be diminished in C57BL/6 males, but not female mice exposed to C6 in utero [7]
We found that C6-exposed XYM fetuses had a significantly smaller CP/CZ ratio when compared to B1-XYM control fetuses (Figure 2C; q = 4.89, P = 0.029, see Table 1 and Supplementary Table 1 for details on statistical tests), which was likely due to a decrease in CP area and not to smaller SP, intermediate zone (IZ) or ventricular zone (VZ)
Summary
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that manifest early in childhood. ASD is characterized by varying degrees of impairment in social interaction and communication, and by restricted interests and repetitive behaviors (DSM-V). In the U.S, about 1 in 59 children was diagnosed with ASD in 2014 [1]. A recent study estimated the heritability of ASD to be 80% [3]. Environmental factors, especially those present during critical periods of prenatal and perinatal brain development, play an essential role in modulating the risk to develop ASD and may account, in part, for the phenotypic variability observed [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
