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.


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.

Reduced Brain Volume in Epilepsy Patients

What’s the science?

Epilepsy is a complex disorder characterized by seizures. The way that brain structure relates to the severity of epilepsy is not well understood. This week in Brain, Whelan and colleagues report structural brain changes in a large sample of epilepsy patients.

How did they do it?

Epilepsy patients were recruited from 24 research centers across 14 different countries. This resulted in 2149 epilepsy patients that were divided into 4 subgroups based on epilepsy type. The patients were scanned using MRI and the brain scans were analyzed to measure brain volumes and cortical thickness (the thickness of the outermost layer of the brain: the cerebral cortex) compared to healthy control participant brains.

What did they find?

They found that in all types of epilepsy, there was reduced brain volume in the right and left thalamus and reduced cortical thickness in the right and left precentral gyrus (motor cortex), which are both important brain regions involved in movement. In the subgroup of medial temporal lobe epilepsy patients, there was reduced brain volume in the hippocampus (a region involved in memory). Lower brain volumes and cortical thickness were associated with a longer duration of epilepsy.


What’s the impact?

This is the largest brain imaging study of epilepsy that has ever been done. Before this study, we didn’t know the extent to which structural brain changes occur in epilepsy. We now know that there are significant structural brain changes in the thalamus and precentral gyrus in epilepsy, which are both very important brain regions for movement and should be investigated further.

C. D. Whelan et al., Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study. Brain. 0, 1–18 (2018). 

Access the original scientific publication here.