Lynette Espino

 Introduction: Serotonin (SERT) plays a role in fetal brain development and mood regulation later in life.¹ The use of Selective Serotonin Reuptake Inhibitors (SSRIs) increases anxiety and depression in mice exposed to SSRIs during an early postnatal period.^1-4 However, children of women who experienced depression during pregnancy also experience behavioral problems and mood disorders.³ For this reason, it is important to understand the changes in fetal brain circuitry that result from SSRI use during pregnancy.⁴ Methods: SERT knockout mice were generated using homologous recombination of a lox-modified SERT gene in PTL1 embryonic stem cells and implanted into target embryonic stem cells in C57BL/6 blastocysts to evaluate the effects on somatosensory cortex.⁵ Mice were bred accordingly for the use of anterograde tracing and array tomography experiments, localization and RNA-sequencing, ontogenetic analysis of cortical projections, and to evaluate the role of cortical vs. raphe S1c6a4/SERT invalidation. Pharmacological experiments and western blot analyses were done to evaluate the effects of SSRI exposure during this critical period.⁶ Women were included who reported depressive or anxiety disorder before or during pregnancy. Children exposed to SSRIs in early, mid-, or late pregnancy were checked for internalizing behaviors at 1.5, 3, and 5 years.⁷ 129S6/SvEvTac mice were used for all experiments and they received either vehicle or fluoxetine during different postnatal windows. Behavioral tests included open field, novelty-suppressed feeding- shock escape, sucrose preference test, forced swim test, and fear conditioning and extinction. Electrophysiology, infralimbic and prelimbic lesions, and histology sections were used to determine changes in mPFC morphology.⁸ Results: These studies suggest that excessive serotonin disrupts the architecture of the somatosensory cortex.^5-6 It results in an increase in connectivity between the prefrontal cortex and dorsal raphe nuclei that are also associated with anxiety and depression.⁶ Use of SSRIs during the 3^rd trimester is more likely to cause behavioral problems in adulthood when compared to SSRI use earlier in pregnancy. ^7-8 Conclusion: Studies show that use of SSRIs during pregnancy alters fetal brain circuitry by increasing connectivity and synapses among different areas. There is need of more research to fully understand what areas of the brain are affected and the consequences they result in.

1. Lugo-Candelas C, Cha J, Hong S, et al. Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy. JAMA Pediatr.2018;172(6):525–533. doi:10.1001/jamapediatrics.2017.5227
2. Brummelte, S., Mc Glanaghy, E., Bonnin, A., & Oberlander, T. F. (2016). Developmental changes in serotonin signaling: Implications for early brain function, behavior and adaptation. Neuroscience, 342, 212-231.
3. Robinson, R., Lahti-Pulkkinen, M., Heinonen, K., Reynolds, R. M., & Räikkönen, K. (2018). Fetal programming of neuropsychiatric disorders by maternal pregnancy depression: A systematic mini review. Pediatric Research, 85(2), 134-145. doi:10.1038/s41390-018-0173-y
4. Frazer, S., Otomo, K., & Dayer, A. (2015). Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes. Translational Psychiatry, 5(9). doi:10.1038/tp.2015.147
5. Chen, X., Ye, R., Gargus, J. J., Blakely, R. D., Dobrenis, K., & Sze, J. Y. (2015). Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development. Cell reports, 10(3), 346–358. doi:10.1016/j.celrep.2014.12.033
6. SoSoiza-Reilly, M., Meye, F. J., Olusakin, J., Telley, L., Petit, E., Chen, X., … Gaspar, P. (2018). SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior. Molecular psychiatry, 10.1038/s41380-018-0260-9. Advance online publication. doi:10.1038/s41380-018-0260-9
7. Lupattelli, A., Wood, M., Ystrom, E., Skurtveit, S., Handal, M., & Nordeng, H. (2018). Effect of Time-Dependent Selective Serotonin Reuptake Inhibitor Antidepressants During Pregnancy on Behavioral, Emotional, and Social Development in Preschool-Aged Children. Journal of the American Academy of Child and Adolescent Psychiatry, 57(3), 200–208. doi:10.1016/j.jaac.2017.12.010
8. Rebello, T. J., Yu, Q., Goodfellow, N. M., Caffrey Cagliostro, M. K., Teissier, A., Morelli, E., … Ansorge, M. S. (2014). Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(37), 12379–12393. doi:10.1523/JNEUROSCI.1020-13.2014