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Abstract
Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.
Highlights
Anti-depressants are commonly prescribed to treat major depression and post-traumatic stress disorder
Prenatal fluoxetine treatment induced deficits in working memory and social recognition We subjected pregnant mice to daily intraperitoneal (i.p.) injections of 0.6 mg/kg FLX or saline (SAL) from embryonic day (ED) 4 to ED19 to examine behavioral changes in mice exposed to Selective serotonin reuptake inhibitor (SSRI) during the prenatal period (Fig. 1a) [21]
The mean number of pups born per litter, percentages of male pups per litter, and average body weights of mice at postnatal day 21 (P21) and P60 were not significantly different between FLX-treated litters and SAL-treated, control litters (Table 1)
Summary
Anti-depressants are commonly prescribed to treat major depression and post-traumatic stress disorder. 17% of pregnant women experience major depression, and approximately 10% of these women use anti-depressants [1,2,3]. The most commonly prescribed anti-depressants, selective serotonin reuptake inhibitors (SSRIs), are believed to increase the ambient level of 5-hydrotryptamine (5-HT, serotonin) in synaptic clefts. Manipulations of brain 5-HT levels during early development produced abnormal neuronal circuit formation in the cortex and promoted aggressive or anxiety-related behaviors [15,16,17,18,19]. The underlying molecular and circuit mechanisms of these behavioral changes have not been investigated and, for this reason, no rescue experiment has been performed in offspring exposed to SSRIs during prenatal period
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