The effects of maternal SSRI exposure on the serotonin system, prefrontal protein expression and behavioral development in male and female offspring rats

Abstract Background Prenatal exposure to selective serotonin reuptake inhibitor (SSRI), such as fluoxetine (FLX) may increase susceptibility to autism spectrum disorder (ASD). However, findings from published studies on SSRI and ASD are inconsistent. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral and ASD-related neurobiological abnormalities in offspring. Methods FLX or normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX=30, NS=27) on gestation day 11 till birth. The resulting offspring were assessed in terms of their physical development and behavior, and underwent in vivo magnetic resonance spectroscopy ( MRS) to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Results The offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety and impaired social interaction. Moreover, down-regulation of 5-HT or SERT expression and up-regulation of TPH levels was observed in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1 H-MRS in the PFC. Finally, a proteomic study revealed sex-dependent differential protein expression. ConclusionsThese findings may have translational importance suggesting that the use of SSRI medication alone in pregnant mothers may result in developmental delay and autistic-like behavior in their offspring. Our results also help to guide the choice of outcome measures in the identification of molecular and developmental mechanisms that may confer vulnerability in ASD.