BrainSpheres: antidepressant yields harmful effects on lab-grown ‘mini-brains’

Written by Heather Jones (Future Science Group)

Using stem cell-derived ‘mini-brains’ grown in the lab (referred to as BrainSpheres in this instance), researchers from Johns Hopkins Bloomberg School of Public Health (MD, USA) have demonstrated that a commonly used antidepressant drug could have damaging effects on the developing human brain.

The study, published in Frontiers in Cellular Neuroscience, also affirms the potential for these BrainSpheres as an alternative model for testing the effects of drugs and other chemicals on the developing brain.

Selective serotonin reuptake inhibitors are commonly used to treat depression during pregnancy, with at least hundreds of millions of prescriptions being taken out annually. One such drug, paroxetine, comes with a warning against use during early pregnancy, with various concerns having been raised about the possible effects of this group of drugs on fetal development. Previous studies have suggested that among other health issues, paroxetine raises the risk of autism.

In this study, researchers used lab-grown ‘mini-brains’, which they termed BrainSpheres, as a model of the developing brain to test the effects of the drug.

“There’s a growing concern that we have an epidemic of neurodevelopmental disorders, including autism, and that these might be caused by exposures to common drugs or other chemicals. However, since traditional animal testing is so expensive, we haven’t been able to properly investigate this question,” commented co-senior author, Thomas Hartung (Bloomberg School).

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The team used adult human cells, typically taken from the skin, and transformed them into stem cells, which they then developed into young brain cells. The resulting tiny clumps of brain tissue, whose cellular mechanisms mimic those of the developing human brain, formed a rudimentary brain-like organization over a period of a few months.

This model could provide a better alternative to animal testing, as not only is it significantly cheaper, but as it involves human cells, it is likely to better represent human pathophysiology.

To test the effects of paroxetine, the team exposed two different sets of BrainSpheres to two different therapeutic blood concentrations of the drug over 8 weeks as the brains continued to develop.

The researchers observed, compare with controls, an 80% decrease in the expression of synaptic markers including synaptophysin, a 60% decrease in neurite outgrowth and a 40–75% decrease in oligodendrocyte cell population.

These results indicate that the drug might induce brain cell development abnormalities and hinder the normal formation of interconnections between developing neurons, which could lead to adverse effects possibly underlying autism or other neurological disorders.

“In this report, we were able to show that testing with mini-brains can reveal relatively subtle neurodevelopmental effects, not just obvious effects, of a chemical,” commented Hartung. “Whether paroxetine causes autism has been a decade-long debate, which could not be settled with animal tests or epidemiological analyses. So we see mini-brains as technology for broader assessment of the risks of common drugs and chemicals, including those that might be contributing to the autism epidemic.”

Sources: Zhong X, Harris G, Smirnova L et al. Antidepressant paroxetine exerts developmental neurotoxicity in an iPSC-derived 3D human brain model. Front. Cell. Neurosci. doi:10.3389/fncel.2020.00025 (2020);