Disrupted serotonin system development via early life antidepressant exposure impairs maternal care and increases serotonin receptor expression in adult female offspring

Unroe, Keaton A.; Maltman, Jessica L.; Shupe, Elizabeth A.; Clinton, Sarah M.

doi:10.1002/dev.22292

Cited by 5 publications

(3 citation statements)

References 76 publications

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“…While the binding pro le of this antidepressant to these receptors is well established [44], no other studies had previously described an altering effect of mirtazapine on the levels of serotonergic and adrenergic receptors. Of note, a recent study showed that early life exposure to the SSRI citalopram, in rats increased mRNA expression of 5HT1A in the medial preoptic area and 5HT1B, 5HT2A and 5HT2C in the prefrontal cortex [45]. More in general, studies on the effects of mirtazapine on speci c protein levels are scant and we only found a study showing that mirtazapine can increase the hepatic CXCL10 chemokine and its cognate receptor CXCR3 [46].…”

Section: Discussionmentioning

confidence: 88%

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

Ciraci,

Santoni,

Tongiorgi

2024

Preprint

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Antidepressants are known for their neurotrophic effects, particularly through the regulation of brain-derived neurotrophic factor (BDNF) expression. Mirtazapine, a tetracyclic noradrenergic and specific serotonergic antidepressant (NaSSA) has been observed to upregulate BDNF, though its underlying mechanism remains unclear. In this study, we used the human neuroblastoma SH-SY5Y cell line to investigate whether mirtazapine could enhance BDNF translation by modulating serotonin and/or norepinephrine and their receptors. A 1-hour stimulation with 1 or 10 µM mirtazapine led to downregulation of serotonergic receptors 5HT1A, while increasing ADRA2A and ADRB2 receptors. Mirtazapine at 10 µM upregulated endogenous BDNF after 3h, but not 1h stimulation. To investigate the translation of major BDNF transcripts, we used chimeric BDNF-luciferase constructs with the untranslated 5'UTR exons I, IIc, IV, or VI, and the long version of the 3'UTR. Luciferase assays and Western blotting revealed that mirtazapine selectively enhanced exon-IIc-BDNF-long3'UTR-Luciferase translation. This increase was associated with norepinephrine release and was inhibited by blocking ADRA2A or ADRB2 adrenoceptors for the exon-IIc-BDNF-long3'UTR-Luciferase, and ADR2B for endogenous BDNF. These findings provide a new perspective on the critical role of the noradrenergic system in mediating mirtazapine’s effects on BDNF translation. We propose a novel mechanism of action in which mirtazapine promotes norepinephrine release and noradrenergic responses by upregulating ADRA2A and ADRB2 while downregulating serotonergic receptors.

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Section: Discussionmentioning

confidence: 88%

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

Ciraci,

Santoni,

Tongiorgi

2024

Preprint

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“…It has recently been shown that female offspring of rats’ dams that were treated during pregnancy and lactation with another SSRI, citalopram, exhibited increased expression of mRNAs for 5-HT1B, 5-HT2A and 5-HT2C receptors in the mPFC (Unroe et al, 2022). Postnatal exposure to citalopram resulted in reduced expression of 5-HT transporter in rat cortex (Maciag et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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

Bobula,

Bąk,

Kania

et al. 2024

Preprint

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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.

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“…Further genetic methods to knock out dSERT during development versus adult flies will be used to address this issue. We note that in mouse models, many effects on behavior seen with both SSRIs and mutants that perturb serotonergic signaling are primarily based on exposure during development [79,[86][87][88][89][90][91].…”

Section: Adult Versus Developmental Effects Of Sert Lofmentioning

confidence: 99%

Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter

Krantz

Bonanno

2023

Preprint

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The transcriptional effects of SSRIs and other serotonergic drugs remain unclear, in part due to the heterogeneity of postsynaptic cells, which may respond differently to changes in serotonergic signaling. Relatively simple model systems such as Drosophila afford more tractable microcircuits in which to investigate these changes in specific cell types. Here, we focus on the mushroom body, an insect brain structure heavily innervated by serotonin and comprised of multiple different but related subtypes of Kenyon cells. We use fluorescence activated cell sorting of Kenyon cells, followed by either or bulk or single cell RNA sequencing to explore the transcriptomic response of these cells to SERT inhibition. We compared the effects of two different Drosophila Serotonin Transporter (dSERT) mutant alleles as well as feeding the SSRI citalapram to adult flies. We find that the genetic architecture associated with one of the mutants contributed to significant artefactual changes in expression. Comparison of differential expression caused by loss of SERT during development versus aged, adult flies, suggests that changes in serotonergic signaling may have relatively stronger effects during development, consistent with behavioral studies in mice. Overall, our experiments revealed limited transcriptomic changes in Kenyon cells, but suggest that different subtypes may respond differently to SERT loss-of-function. Further work exploring the effects of SERT loss-of-function in other Drosophila circuits may be used help to elucidate how SSRIs differentially affect a variety of different neuronal subtypes both during development and in adults.

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Disrupted serotonin system development via early life antidepressant exposure impairs maternal care and increases serotonin receptor expression in adult female offspring

Cited by 5 publications

References 76 publications

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

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

Transcriptional changes in specific subsets of Drosophila neurons following inhibition of the serotonin transporter

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