Abstract
Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with the emergence of the behavioral phenotype. Genome-wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated (that is, differentially methylated sites, DMSs) by the adverse environment in ventral-hippocampal granule cells, neurons that can be linked to the anxiety phenotype. DMSs were typically clustered and these clusters were preferentially located at gene bodies. Although CpGs are typically either highly methylated or unmethylated, DMSs had an intermediate (20–80%) methylation level that may contribute to their sensitivity to environmental adversity. The adverse maternal environment resulted in either hyper or hypomethylation at DMSs. Clusters of DMSs were enriched in genes that encode cell adhesion molecules and neurotransmitter receptors; some of which were also downregulated, indicating multiple functional deficits at the synapse in adversity. Pharmacological and genetic evidence links many of these genes to anxiety.
Highlights
A significant factor in the development of psychiatric disorders, including anxiety, depression, autism and attention deficit hyperactivity disorder (ADHD) is the environment, both prenatally and during early postnatal life.[1,2] Early life adversity, such as maternal stress, maternal infection[3] and maternal separation during early postnatal life,[4] and its behavioral consequences on the offspring can be reproduced in nonhuman primates and rodents
As anxiety in the offspring of 5-HT1AR-deficient mothers is associated with the delayed maturation of v-dentate granule cells (DGCs) during early postnatal life, and because genetic interference with v-DGC maturation is accompanied by
Pre and early postnatal adversity is a major factor in the development of psychiatric conditions
Summary
A significant factor in the development of psychiatric disorders, including anxiety, depression, autism and attention deficit hyperactivity disorder (ADHD) is the environment, both prenatally and during early postnatal life.[1,2] Early life adversity, such as maternal stress, maternal infection (for example, immune activation during pregnancy)[3] and maternal separation during early postnatal life,[4] and its behavioral consequences on the offspring can be reproduced in nonhuman primates and rodents. Via the entorhinal cortex, arrive to v-DGCs that are connected to v-CA3 and v-CA1 neurons, which together form the classical trisynaptic HIP circuit This circuit sends direct projections to the medial prefrontal cortex and activity in the v-HIP is synchronized with medial prefrontal cortex to produce appropriate defensive and anxiety-related behaviors.[14] Other connections of v-HIP that are relevant to anxiety include those to the amygdala and the bed nuclei of stria terminalis.[15]. Current knowledge on neuronal methylation is largely limited to whole brain[21,22] and in vitro differentiated neurons/neuronal precursors,[23,24] the methylation pattern of mouse DGCs has recently been reported.[20] the effect of early environmental influences on neuronal DNA methylation has mostly been tested with candidate genes,[19,25] an approach that does not provide an unbiased survey of epigenetic changes induced by maternal adversity. Methylation changes tended to be clustered and the affected genes encode proteins involved in synapse formation and function
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