Brazilian scientists are proposing to conduct experiments on lab-grown mini-brains to study the effects of drugs on fetal brain development.
Depression affects a significant proportion of pregnant women worldwide, with estimates ranging from 10% to 16%. While most women can improve with the help of antidepressants, the effects of these drugs on fetal brain development are not fully understood.
Brazilian researchers reviewed over 100 scientific articles on the subject and concluded that advanced techniques such as genomics should be used to study the effects of antidepressants, particularly sertraline, the world’s most prescribed antidepressant. Although scientific evidence supports the safety of using these drugs during pregnancy, more research is needed to fully understand their effects on fetal neurodevelopment.
“Most of the papers we reviewed were reports of observational studies and studies performed in the laboratory on cell cultures and animals whose brain development is very different from that of humans. They do not provide enough data to warrant conclusive results,” said neuroscientist Alexandre Kihara, a researcher at the Federal University of the ABC (UFABC) Laboratory of Neurogenetics in São Bernardo do Campo, São Paulo state.
“We propose an experimental trial model using human-induced pluripotent stem cells [hiPSC] to study what happens to fetal nerve cell development in pregnant women during treatment with antidepressants,” said Luciana Rafagnin Marinho, a researcher at UFABC with doctoral and postdoctoral qualifications in epigenetics, in vitro embryo production and animal reproduction.
Marinho and Kihara are the first and last authors, respectively, of the review article recently published in the journal Seminars in cell and developmental biology. The study was supported by FAPESP.
Human-made pluripotent stem cells can be differentiated into brain organoids (“mini-brains”), which scientists want to use for research into neurodegenerative diseases such as Parkinson’s[{” attribute=””>Alzheimer’s, and in the testing of drugs with neurological action.
“These structures can be used to test different dosages and track the development of brain cells up to the third trimester,” said Alysson Muotri, penultimate author of the article. Muotri is a neuroscientist at the University of California San Diego (UCSD) in the United States and heads a genetics laboratory that has pioneered the development of brain organoids to study autism and other neurological disorders. He is also a co-founder of Tismoo, a Brazilian biotech startup.
“We can study the organoids for up to a year, observing aspects of their development such as the morphology and electrophysiology of individual neurons or neural networks,” he explained.
To exemplify the possible advances, Marinho cited the only study that used brain organoids among the more than 100 covered by the review. “It investigated the effects of paroxetine and detected a reduction in the growth of neurites [ projections from neurons that develop into axons and dendrites to form complex circuits ] and the population of oligodendrocytes, which produce the myelin sheath around the axons and are therefore important for information to travel through the nervous system,” she said.
The scientists note that sequencing the whole genome, analyzing the transcriptome and single cells[{” attribute=””>RNA sequencing apply to research using organoids. “The technology enables us to investigate the effects of exposure to antidepressants on different cell types, such as progenitor cells, glial cells, and neurons. This is particularly important because alterations may not be confined to neurons. We need to know all these implications,” Kihara said.
Caution is required in interpreting the findings of this kind of research. “We’re not saying antidepressants shouldn’t be used in pregnancy. We’re proposing an experimental model and stressing the need to study their effects on neurodevelopment with the most advanced resources available so that potential alterations can be managed,” Kihara said.
Reference: “The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools” by Luciana Simões Rafagnin Marinho, Gabrielly Maria Denadai Chiarantin, Juliane Midori Ikebara, Débora Sterzeck Cardoso, Théo Henrique de Lima-Vasconcellos, Guilherme Shigueto Vilar Higa, Mariana Sacrini Ayres Ferraz, Roberto De Pasquale, Silvia Honda Takada, Fabio Papes, Alysson R. Muotri and Alexandre Hiroaki Kihara, 15 September 2022, .
DOI: 10.1016/j.semcdb.2022.09.007