Maternal fluoxetine impairs synaptic transmission and plasticity in the medial prefrontal cortex and alters the structure and function of dorsal raphe nucleus neurons in offspring mice

Abstract

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are a class of antidepressant drugs commonly prescribed to women during pregnancy and breastfeeding to treat depression. There is evidence that prenatal exposure to SSRIs may be associated with a higher risk of adverse cognitive outcomes and affective disorders in later life. In animal models, exposure to SSRIs during brain development results in behavioral alterations as well as structural abnormalities of cerebral cortical neurons. Little is known about the consequences of SSRI- induced excess of 5-HT during development on the brain serotonergic system itself. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6J mouse dams during pregnancy and lactation. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated induction of long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring. Whole-cell recordings demonstrated no changes in the excitability of DRN 5-HT neurons in FLX-exposed offspring of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetic characteristics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Regarding side effects on brain development, vortioxetine might be a safer alternative to FLX.