Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

Abstract

SummaryPrenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.

Transplantation of mesenchymal stem cells reverses behavioural deficits and impaired neurogenesis caused by prenatal exposure to valproic acid

“…Specifically, Juliandi et al (2015) reported that prenatal exposure to VPA increased embryonal cortical neurogenesis but decreased a long-term adult hippocampal neurogenesis [16]. They also reported on aberrant morphological characteristics of DG DCX(+) neurons.…”

“…It was also shown that physical activity could partially restore neurogenesis and cognitive deficits caused by the developmental exposure to VPA [16]. …”

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…*P b 0.05; **P b 0.01; NS, not significant. hippocampus (Juliandi et al, 2015), so we checked the Wnt signaling and mTOR signaling in these brain tissues of VPA-exposed rat. Our study shows that Wnt signaling and mTOR signaling are activated in the brain tissues of VPA-exposed rats.…”

c-Jun Amino-Terminal Kinase is Involved in Valproic Acid-Mediated Neuronal Differentiation of Mouse Embryonic NSCs and Neurite Outgrowth of NSC-Derived Neurons

“…Indeed, our study demonstrated that VPA increased the percentage of β-III-tubulin- or MAP-2-positive neurons. However, a previous study has found that VPA-treated mice (300 mg/kg) have a decreased level of postnatal neurogenesis in the hippocampus, this is presumably due to a slower differentiation of the residual NPCs caused by depletion of the NPC pool [48]. These seemingly contradictory findings could imply that VPA-mediated various effects might depend on the cell type, context of VPA usage, and experimental design used.…”