Brain organoids reveal effect of sodium valproate on prenatal brain

New research using brain organoids suggests that stem cell senescence, where cells are halted in a suspended state, is responsible for the fetal brain changes caused by sodium valproate.

Used in the treatment of epilepsy, bipolar disorder and migraines, sodium valproate can result in children with cognitive defects, microcephaly (small head size) and autism if taken during pregnancy. This study, published in PLOS Biology, suggests that senescence of certain brain cells could be responsible for developmental abnormalities leading to some of these conditions.

While cellular senescence has long been associated with ageing and age-related disease, we now show that aberrant induction of senescence can also contribute to developmental defects' said first author Dr Muriel Rhinn of the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

During early embryo development, brain stem cells called neuroepithelial cells proliferate in the neural tube and differentiate into the neurons and glia cells that make up the brain. In this study, researchers examined mouse embryos that had been exposed to sodium valproate and found that they had lower levels proliferation of these brain stem cells than normal mouse embryos.

Using brain organoids, mini brains grown from human stem cells, researchers attempted to see if they could reproduce these results in model human brains. Treatment of these organoids with sodium valproate at different time points resulted in smaller brain organoids with fewer neurons. Further analysis showed that sodium valproate activated a molecule called p14ARF, inducing senescence in the neuroepithelial brain stem cells and restricting their growth.

Further exploring this effect, experiments in mice lacking p19ARF (the mouse equivalent of p14ARF) showed that the absence of this gene protected sodium valproate treated mice from microcephaly and changes in gene expression patterns that are associated with autism. However, this did not protect against other defects observed with sodium valproate, including spinal cord deformities, suggesting that other pathways are also involved.

Sodium valproate prescribing to women of childbearing age has been the focus of numerous inquiries around the world, many following campaigning by families affected by the disabilities caused by prenatal exposure.

Recent investigations have shown that despite guidelines in the UK that outline the drug should not be given to pregnant women and should only be given to women of childbearing age when there is no alternative, six babies a month are still being born to women who had been given the drug while pregnant the Medicines and Healthcare Products Regulatory Agency told the Times.

The newspaper reported this week that there were now concerns that genetic changes caused by exposure to the drug posed a 'transgenerational risk'.

Professor Peter Turnpenny, a consultant clinical geneticist at the Royal Devon University Healthcare NHS Foundation Trust told the Times: 'The main research at the moment has focused on animal models such as rodents and mice, and this is showing there may be a transgenerational effect. That doesn’t mean it will be the same in humans, but it should be enough to say we need to look at this with a properly funded study into a substantial human cohort.'