Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors

Abstract

Purpose: Associations have been made between maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy and altered behavior in offspring, including an increased risk of autism. Given the important role serotonin plays in behavior, we hypothesized SSRI exposure in the perinatal period would alter central serotonin receptor expression and program adult behaviors in mice. Methods: Female mice were injected with sertraline or saline throughout pregnancy. Offspring continued to receive injections on postnatal days 1–14, a time period in mice similar to the third trimester in human pregnancy. Adult offspring underwent behavioral testing and serotonin receptor mRNA levels were quantified. Results: Compared to controls, SSRI exposed mice did not have a reduction in social interactions, spatial learning, or exploratory behavior. As adults, sertraline exposed mice had significantly increased mRNA levels of multiple 5-HT receptors, serotonin transporter (5-HTT), and tryptophan hydroxylase isoform 2 in the cerebral cortex. Conclusion: Although no behavioral phenotype was observed, SSRI exposure in the perinatal period permanently alters cerebral receptor mRNA levels. We speculate these shifts in mRNA expression provide important compensation during SSRI exposure. Further pre-clinical and clinical investigation into additional serotonin-regulated phenotypes is necessary to further assess the long-term implications of perinatal SSRI exposure.

Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies

“…The serotonin system consists of 15 different receptors that are key players at crucial neurodevelopmental stages, regulating neurogenesis, apoptosis, axon branching and dendritogenesis 11 . Many of the studies included in the synthesis of evidence in the current review, which have been selected on the presence of behavioral outcomes, also include outcomes reflecting brain health from the global to the molecular level: the corticosterone response to stress 74, 81, 96, 100, 123, 124, 126, 130, 135 , brain structure and connectivity 71, 77, 84, 93, 101, 110, 122 , neuronal health 59, 82, 85, 89, 104, 109, 111, 126, 135 , monoamine concentrations in the brain 43, 44, 46, 59, 105, 116, 117, 133, 135, 140, 141 , protein expression in the brain – mainly related to the serotonergic system and neurogenesis 62, 71, 78, 88, 91, 97, 127, 129, 141 , gene expression 76, 94, 96, 112, 113, 120, 121, 123, 137, 141, 143 , and epigenetic modifications 76, 112, 114, 124 .…”

Brain hyperserotonemia causes autism-relevant social deficits in mice

“…Evidence suggests that prenatal exposure to SSRIs increases the risk of ASD in humans [ 49 , 50 ]. However, the behavioral effects of prenatal exposure to SSRIs are controversial in mice and rats [ 51 – 53 ]. There may be critical periods during which the developing brain is particularly vulnerable to elevated 5-HT function that are not addressed by reductions in Sert expression here that occurred throughout the lifespan.…”

Pre-reproductive stress and fluoxetine treatment in rats affect offspring A-to-I RNA editing, gene expression and social behavior

“…6 ). Assuming that pre-gestationally administered FLX had a direct effect on the developing fetus, this finding can be explained by the known effects of perinatal FLX administration on the developing serotonergic system [ 102 ]. A sexually dimorphic effect of pre- or perinatal SSRI exposure on social behavior has been previously reported (see [ 103 ] for review).…”