Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice

atsuhiko sakai, Taito Matsuda, Hiroyoshi Doi, Yukiko Nagaishi, Kiyoko Kato, Kinichi Nakashima

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5 Citations (Scopus)

Abstract

Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.

Original languageEnglish
Pages (from-to)4270-4275
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number16
DOIs
Publication statusPublished - Apr 17 2018

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Neurogenesis
Valproic Acid
Anticonvulsants
Seizures
Neural Stem Cells
CXCR4 Receptors
Stem Cells
Neurons
Newborn Infant
Hippocampus
Exercise
Adult Children
Nervous System Diseases
Running
Cell Movement
Pregnant Women
Epilepsy
Gene Expression
Pregnancy
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice",
abstract = "Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7{\%} of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.",
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AU - sakai, atsuhiko

AU - Matsuda, Taito

AU - Doi, Hiroyoshi

AU - Nagaishi, Yukiko

AU - Kato, Kiyoko

AU - Nakashima, Kinichi

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