Peripartum sertraline impacts maternal neurobehavioral and neurodegenerative mechanisms in pregnant and postpartum mice

Abstract Selective Serotonin Reuptake Inhibitors (SSRIs) are among the most common medications used for depression in postpartum and lactating people, who experience increased depression risk. However, there is a limited understanding of peripartum SSRI impacts on maternal neurobehavioral responses, and particularly those of sertraline, the most prescribed SSRI in United States (US) pregnancies. We administered C57Bl/6 females sertraline via a non-invasive, naturalistic approach (167 mg/L drinking water) from 2 weeks pre-conception through lactation (PND21) or for an equivalent duration in nonpregnant controls. We assessed behavior and molecular brain changes intrapartum and postpartum at ~1 year of age. Chronic sertraline reduced depressive- and anxiety-like behaviors. Pregnancy itself decreased anxiety-like and hedonic behaviors. RNA sequencing of maternal brain revealed only 52 differentially expressed genes (DEGs) in frontal cortex with sertraline. These DEGs over-represented functions related to immunity. In contrast, sertraline altered 962 targets in maternal hypothalamic paraventricular nucleus, with DEGs overrepresenting neurotransmission and neurodegeneration. We then discontinued sertraline and aged animals to approximately 1 year to test neurodegenerative phenotypes. Having one prior litter, regardless of peripartum sertraline, improved aged females' spatial learning and memory. Sertraline, regardless of postpartum status, improved working memory. Further, we found buffering of neurodegeneration-related gene network changes and increased excitatory synapse density in the hippocampus after peripartum sertraline. Peripartum sertraline alters maternal neurobiology and behavior in pregnancy and beyond, with long-term benefits to neurodegenerative processes. Pregnancy also exerts its own, lasting effects on learning and memory. These findings might be exploited in the future to abrogate neurodegenerative disease.