Interplay between maternal Slc6a4 mutation and prenatal stress: a possible mechanism for autistic behavior development

• Published in: Scientific reports Vol. 7; no. 1; pp. 8735 - 12
• Main Authors: Sjaarda, Calvin P., Hecht, Patrick, McNaughton, Amy J. M., Zhou, Audrina, Hudson, Melissa L., Will, Matt J., Smith, Garth, Ayub, Muhammad, Liang, Ping, Chen, Nansheng, Beversdorf, David, Liu, Xudong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-08-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 38/90; 38/91; 45/22; 45/23; 45/77; 631/208/176/1988; 631/208/191/2018; 631/378/1689/1373; 64/60; 692/699/476/1373; Alleles; Animals; Autism; Autistic Disorder - etiology; Behavior, Animal; Brain - metabolism; Children; Computational Biology; Disease Models, Animal; DNA Methylation; Embryos; Female; Gene expression; Gene Expression Profiling; Genomes; Genotype; Humanities and Social Sciences; Male; Maternal Exposure - adverse effects; Mice; Mice, Knockout; MicroRNAs - genetics; miRNA; Models, Biological; multidisciplinary; Mutation; Offspring; Pregnancy; Prenatal experience; Prenatal Exposure Delayed Effects; RNA, Messenger - genetics; Science; Science (multidisciplinary); Serotonin; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin transporter; Stress, Psychological - complications; Transcriptome
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-07405-3

The low activity allele of the maternal polymorphism, 5HTTLPR, in the serotonin transporter,
SLC6A4
, coupled with prenatal stress is reported to increase the risk for children to develop autism spectrum disorder (ASD). Similarly, maternal
Slc6a4
knock-out and prenatal stress in rodents results in offspring demonstrating ASD-like characteristics. The present study uses an integrative genomics approach to explore mechanistic changes in early brain development in mouse embryos exposed to this maternal gene-environment phenomenon. Restraint stress was applied to pregnant
Slc6a4
+/+
and
Slc6a4
+/−
mice and post-stress embryonic brains were assessed for whole genome level profiling of methylome, transcriptome and miRNA using Next Generation Sequencing. Embryos of stressed
Slc6a4
+/+
dams exhibited significantly altered methylation profiles and differential expression of 157 miRNAs and 1009 genes affecting neuron development and cellular adhesion pathways, which may function as a coping mechanism to prenatal stress. In striking contrast, the response of embryos of stressed
Slc6a4
+/−
dams was found to be attenuated, shown by significantly reduced numbers of differentially expressed genes (458) and miRNA (0) and genome hypermethylation. This attenuated response may pose increased risks on typical brain development resulting in development of ASD-like characteristics in offspring of mothers with deficits in serotonin related pathways during stressful pregnancies.