Past neuroscience studies have consistently showed the profound effects of early life experiences on the brain’s wiring, particularly on the formation of the junctions that enable communication between neurons (i.e., synapses). The influence of early life experiences was found to be particularly pronounced during so-called sensitive periods (SPs), windows of time during which the brain’s plasticity (i.e., its ability to form or reorganize neural connections) is heightened.
Experimental evidence suggests that these periods of heightened brain plasticity are regulated by specialized neurons that release the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). So-called parvalbumin-positive (PV+) interneurons have been found to play a central role in the unfolding of SPs, as their gradual enclosure into protective structures was linked to the conclusion of these periods.
Researchers at University of Milan and University of Helsinki recently carried out a study exploring the effects of early exposure to the widely prescribed antidepressant fluoxetine (FLX) on the regulation of SPs in rats. Their findings, published in Molecular Psychiatry, suggest that exposure to fluoxetine during gestation, pregnancy or breastfeeding could influence the brain development and behavior of rat pups later in life.
“Early-life experiences shape neural networks, with heightened plasticity during the so-called ‘sensitive periods’ (SPs),” wrote Maria Teresa Gallo, Anais Virenque and their colleagues in their paper. “SPs are regulated by the maturation of GABAergic PV+ interneurons, which become enwrapped by perineuronal nets (PNNs) over time, modulating SP closure. Additionally, the opening and closing of SP are orchestrated by two distinct gene clusters known as ‘trigger’ and ‘brake.'”
Past research identified two broad groups of genes that either initiate heightened periods of brain plasticity (i.e., SPs) or close them. Trigger genes were found to prompt the opening of SPs, while “brake” genes their conclusion.
Changes in these genetic mechanisms were linked to the emergence of various neuropsychiatric conditions. The main objective of the recent work by Gallo, Virenque and their colleagues was to investigate the possible effects of pre-natal and early life rat exposure to the drug FLX on the processes regulating the opening and closing of SPs.
FLX is among the most prescribed selective serotonin reuptake inhibitors (SSRIs). These are pharmaceutical drugs that can treat the symptoms of depression and other mental health disorders by increasing the activity of serotonin in the brain.
“We investigate, in rats, whether the behavioral phenotypes observed in adults exposed to FLX during gestation or breastfeeding (until postnatal day 21) are due to alterations in SP dynamics,” wrote Gallo, Virenque and their colleagues. “In line with the pathological-like adult phenotypes observed, the molecular results reveal a clear sex difference with significant changes in the density of PV+, in the proportion of PV+ cells surrounded by PNNs, as well as in the expression of trigger and brake genes across the lifespan, in the prefrontal cortex and dorsal hippocampus.”
The researchers found that the exposure to FLX during gestation (i.e., when pups were still developing in the womb) and breastfeeding had distinct effects on the timing with which SPs unfolded later in life. Specifically, the SPs of male rats exposed to the drug appeared to open earlier than usual, while those of exposed female rats were delayed.
“We observed the strongest effect in the dentate gyrus (DG) of the dorsal hippocampus, with an anticipation in prenatal-FLX males and a delay in postnatal-FLX females of SP opening,” wrote the authors. “We suggest that the molecular targets herein described may represent useful biomarkers to identify people with potentially increased vulnerability and, accordingly, we can hypothesize that strategies (pharmacological or not) aimed at correcting these abnormalities may be useful in preventing the pathological manifestation.”
The results gathered by this research team hint at the possibility that a mother’s intake of FLX during pregnancy could have long-term effects on the development of their offspring’s brain, potentially increasing the risk that they will develop neurodevelopmental or psychiatric disorders. To have clinical implications, however, they should be validated in human populations.
In the future, the findings could shed further light on the neural and genetic mechanisms underpinning brain development and the establishment of important neural connections. This could in turn help to devise new protocols or guidelines to promote the brain’s healthy development from the earliest stages of life.
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More information:
Maria Teresa Gallo et al, From early-life fluoxetine exposure to lifelong, sex-specific behavioral changes: decoding the dynamics of sensitive periods, Molecular Psychiatry (2025). DOI: 10.1038/s41380-025-03223-6
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Early intake of the antidepressant fluoxetine alters brain development in rats, study finds (2025, October 2)
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