Prenatal stress and fluoxetine exposure in mice differentially affect repetitive behaviors and synaptic plasticity in adult male and female offspring

Autism spectrum disorder (ASD) is characterized by social communication impairments with restricted and repetitive behaviors (RRBs). The increase in prevalence of ASD and the heterogeneity of symptom severity may arise from a complex interaction of environmental and genetic factors that alter synaptic plasticity. Maternal stress during pregnancy, which is linked to depression, may be one risk factor for an ASD phenotype in offspring. Selective serotonin reuptake inhibitor (SSRI) treatment can be effective in alleviating maternal depression but prenatal SSRI exposure itself may be a risk factor for autism in offspring. The present study investigated in C57BL/6J pregnant mice whether restraint stress (G4-18) and/or treatment with the SSRI fluoxetine (G8-18) affects autism-related behaviors and hippocampal synaptic plasticity in male and female offspring. The findings indicate that restraint stress reduces preference for sucrose reward in pregnant dams that is reversed by fluoxetine. In adult male offspring, combined prenatal stress and SSRI exposure increased self-grooming and impaired spatial reversal learning. In adult female offspring, the prenatal experiences did not affect self-grooming, but restraint stress alone or SSRI exposure alone impaired spatial reversal learning. Prenatal stress reduced anxietyrelated behavior in male and female offspring. Further, LTP induced by theta-burst stimulation of Schaffercommissural afferents in field CA1 was significantly reduced in female offspring exposed to prenatal stress alone or combination with fluoxetine. Together, these findings suggest that exposure to prenatal stress, SSRI treatment or the combination differentially affects male and female offspring in autism-like behaviors and synaptic plasticity.

Automated summary

Autism spectrum disorder (ASD) is characterized by social communication impairments and restricted and repetitive behaviors (RRBs). Maternal stress during pregnancy and selective serotonin reuptake inhibitor (SSRI) treatment may affect autism-related behaviors and synaptic plasticity in offspring. This study found that prenatal stress and SSRI exposure increased self-grooming and impaired spatial reversal learning in male offspring, whereas in female offspring, prenatal stress or SSRI exposure impaired spatial reversal learning. Prenatal stress reduced anxiety-related behavior in both male and female offspring, and synaptic plasticity was affected in female offspring.