Sertraline-Induced 5-HT Dysregulation in Mouse Cardiomyocytes and the Impact on Calcium Handling.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 15% of pregnancies in the United States for depression. Maternal use of SSRIs has been linked to an increased risk of congenital heart defects, but the exact mechanism of pathogenesis is unknown. SSRIs, including sertraline, are permeable to the placenta and can produce direct fetal exposure. Previously, we have shown decreased cardiomyocyte proliferation, left ventricle size, and cardiac expression of the serotonin receptor 5-HT_2B in offspring of mice exposed to the SSRI sertraline relative to offspring of saline-exposed mice. Using a mouse model of in utero plus neonatal sertraline exposure, we observed lengthened peak-to-peak time of calcium oscillation (saline 784 ±76 ms; sertraline 1121 ± 130 ms, p<0.001) and decreased expression of critical genes in calcium regulation. We also observed significant up-regulation of specific miRNAs that modulate serotonin signaling in neonatal cardiac tissues (Slc6a4: miR-223-5p, miR-92a-2-5p, miR-182-5p; Htr2a: miR-34b-5p, miR-182-5p; Htr2b: miR-223-5p, miR-92a-2-5p, miR-337-5p) (p<0.05) with corresponding levels of the target mRNAs down-regulated (Slc6a4 0.73 ± 0.05; Htr2a 0.67 ± 0.04; Htr2b 0.72 ± 0.03; all p< 0.01), resulting in decreased production of the cognate proteins. Adult mice at 10 weeks showed altered cardiac parameters including decreased heart rates in males (saline 683 ± 8 vs sertraline 666 ± 6 beats per minute, p< 0.05) and ejection fraction in females (saline 83.9 ± 0.6% vs sertraline 80.6 ± 1.1%, p<0.05). These findings raise the question if sertraline exposure during development may increase the potential risk for cardiac disease when subjected to stress.