Antiepileptic Drugs Induce Mislocalization of Neurons in the Hippocampus

What's the science?

Valproic acid is an anti-epileptic drug prescribed to some pregnant women who have epilepsy. Use of the drug during pregnancy is associated with autism and Attention Deficit Hyperactivity Disorder in offspring, and these disorders are associated with a higher risk for seizures. High seizure risk has also been linked to mislocalized neural stem cells/progenitor cells in the hippocampus (which will become neurons in the hippocampus; a brain region involved in learning and memory). This week in PNAS, Sakai and colleagues explored whether exposure to valproic acid increased seizure susceptibility through hippocampal mechanisms in mice.

How did they do it?

To test whether exposure to valproic acid could cause seizures, they gave kainic acid (activates glutamate receptors and can promote seizure activity) to mice (at 12 weeks old) who had or had not been previously exposed to valproic acid prenatally. They used immunohistochemistry to locate progenitor cells in these mice. Next they used RNA-sequencing of neural stem cells/progenitor cells in the hippocampus at embryonic day 15, postnatal day 5, and 12 weeks old to identify differentially expressed genes whose expression levels varied due to prenatal valproic acid exposure at embryonic day 12, 13, and 14 (3 times). They then matched abnormal gene expression to known gene function (Gene Ontology analysis). Finally, they examined whether exercise (voluntary running) might mitigate the effects of valproic acid on seizure activity, due to its known role in neurogenesis (production of new neurons).

What did they find?

Mice exposed to valproic acid experienced increased susceptibility to seizures at 12 weeks of age, and increased mislocalization of newly generated neurons from stem cells/progenitor cells within the dentate gyrus (decreased in the granule cell layer, increased at the hilus). Several differentially expressed genes were present at different developmental stages in mice exposed to valproic acid, indicating that valproic acid affects gene expression in stem cells/progenitor cells the hippocampus. Using Gene Ontology, they identified several genes involved in cell and neuronal migration, including Cxcr4. When mice exposed to valproic acid voluntarily exercised (ran) for eight weeks, their susceptibility to seizures decreased and their Cxcr4 expression normalized, indicating that exercise may mitigate the effects of valproic acid on the hippocampus through Cxcr4.

 Artistic rendering of Figure 1c

Artistic rendering of Figure 1c

What's the impact?

This is the first study to link valproic acid with mislocalization of hippocampal neurons and seizure susceptibility in the offspring of pregnant mice. We now have a better understanding of the mechanisms underlying the harmful effects of valproic acid. Exercise may be a particular avenue for focus, as it may mitigate the effects of improper hippocampal neuron placement on susceptibility to seizures.

naka.png

A. Sakai et al., Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice. PNAS (2018). Access the original scientific publication here.