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

ABSTRACT: 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.

SUBMITTER: Sjaarda CP

PROVIDER: S-EPMC5562880 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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

Sjaarda Calvin P CP Hecht Patrick P McNaughton Amy J M AJM Zhou Audrina A Hudson Melissa L ML Will Matt J MJ Smith Garth G Ayub Muhammad M Liang Ping P Chen Nansheng N Beversdorf David D Liu Xudong X

Scientific reports 20170818 1

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 mater ...[more]

PMID: 28821725

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Project description:The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions.

Project description:Although maternal stress during pregnancy and even before conception shapes offspring risk for mental health problems, relatively little is known about the mechanisms through which these associations operate. In theory, preconception and prenatal stress may affect offspring mental health by influencing child responses to postnatal caregiving. To address this knowledge gap, this study had two aims. First, we examined associations between preconception and prenatal stress with child temperament profiles at age four using multilevel assessment of maternal perceived stress and stress physiology. Second, we tested child temperament profiles as moderators of associations between observed parenting behaviors during a parent-child free-play interaction when children were 4 years old and child behavior problems 1 year later. Latent profile analyses yielded four distinct child temperament profiles: inhibited, exuberant, regulated low reactive, and regulated high reactive. Consistent with hypotheses, preconception, and prenatal stress each independently predicted the likelihood of children having temperament profiles characterized by higher negative emotionality and lower regulation. Specifically, preconception perceived stress and prenatal cortisol predicted likelihood of children having an exuberant temperament, whereas prenatal perceived stress predicted likelihood of children having an inhibited temperament. Contrary to hypotheses, temperament profiles did not moderate predictions of child behavior problems from observed parenting behaviors; however, responsive parenting behaviors inversely predicted child behavior problems independently of child temperament. These findings add to growing evidence regarding effects of preconception factors on child outcomes and underscore a central role for responsive parenting behaviors in predicting more favorable child mental health independent of child temperament. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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

Publications

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

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