Perinatal exposure to the SSRI paroxetine alters the methylome landscape of the developing dentate gyrus

Abstract

Evidence in humans and rodents suggests that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can have serious long‐term consequences in offspring exposed in utero or infancy via breast milk. In spite of this, there is limited knowledge of how perinatal SSRI exposure impacts brain development and adult behaviour. Children exposed to SSRIs in utero exhibit increased internalizing behaviour and abnormal social behaviour between the ages of 3 and 6, and increased risk of depression in adolescence; however, the neurobiological changes underlying this behaviour are poorly understood. In rodents, perinatal SSRI exposure perturbs hippocampal gene expression and alters adult emotional behaviour (including increased depression‐like behaviour). The present study demonstrates that perinatal exposure to the SSRI paroxetine leads to DNA hypomethylation and reduces DNA methyltransferase 3a (Dnmt3a) mRNA expression in the hippocampus during the second and third weeks of life. Next‐generation sequencing identified numerous differentially methylated genomic regions, including altered methylation and transcription of several dendritogenesis‐related genes. We then tested the hypothesis that transiently decreasing Dnmt3a expression in the early postnatal hippocampus would mimic the behavioural effects of perinatal SSRI exposure. We found that siRNA‐mediated knockdown of Dnmt3a in the dentate gyrus during the second to third week of life produced greater depression‐like behaviour in adult female (but not male) offspring, akin to the behavioural consequences of perinatal SSRI exposure. Overall, these data suggest that perinatal SSRI exposure may increase depression‐like behaviours, at least in part, through reduced Dnmt3a expression in the developing hippocampus.

Neonatal resource scarcity alters maternal care and impacts offspring core temperature and growth in rats

“…Porsolt's FST was performed as previously described across two sessions (Glover et al., 2019) using Plexiglas cylindrical containers (45 cm height × 20 cm diameter). On both days, water depth was approximately 30 cm and the temperature was 25°C.…”

“…Porsolt's FST was performed as previously described across two sessions (Glover et al, 2019) using Plexiglas cylindrical containers (45 cm height × 20 cm diameter). On both days, water depth was approximately 30 cm and the temperature was 25 • C. Immobility in this test has been regarded as an indicator of passive coping or behavioral despair (Commons et al, 2017;Porsolt et al, 1977).…”

Inborn differences in emotional behavior coincide with alterations in hypothalamic paraventricular motor projections

“…Porsolt's FST was performed as previously described with 30‐cm deep 25°C water in Plexiglas containers (45 cm high × 20 cm diameter) (Glover et al., 2019; Nam et al., 2014). On FST day 1, rats were placed (1/cylinder) into the water for 15 min.…”

Disrupted serotonin system development via early life antidepressant exposure impairs maternal care and increases serotonin receptor expression in adult female offspring

“…The housekeeping genes used for this study were: Abl1 (Rn01436237_m1) and Gapdh (Rn01775763_g1). Relative fold changes between experimental groups were compared for a given gene at a particular time point were calculated using the ΔΔCT method (Glover et al., 2019).…”

“…Water intake and animal weight were monitored daily, and drug concentrations were adjusted to maintain a steady dose. We previously used this drug in drinking water approach with another SSRI (paroxetine) and demonstrated that the dose and administration method are sufficient to achieve detectable drug levels in pups’ blood and brain tissue (Glover et al., 2015; 2019).…”