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The Proliferation of Dentate Gyrus Progenitors in the Ferret Hippocampus by Neonatal Exposure to Valproic Acid.

ABSTRACT: Prenatal and neonatal exposure to valproic acid (VPA) is associated with human autism spectrum disorder (ASD) and can alter the development of several brain regions, such as the cerebral cortex, cerebellum, and amygdala. Neonatal VPA exposure induces ASD-like behavioral abnormalities in a gyrencephalic mammal, ferret, but it has not been evaluated in brain regions other than the cerebral cortex in this animal. This study aimed to facilitate a comprehensive understanding of brain abnormalities induced by developmental VPA exposure in ferrets. We examined gross structural changes in the hippocampus and tracked proliferative cells by 5-bromo-2-deoxyuridine (BrdU) labeling following VPA administration to ferret infants on postnatal days (PDs) 6 and 7 at 200 μg/g of body weight. Ex vivo short repetition time/time to echo magnetic resonance imaging (MRI) with high spatial resolution at 7-T was obtained from the fixed brain of PD 20 ferrets. The hippocampal volume estimated using MRI-based volumetry was not significantly different between the two groups of ferrets, and optical comparisons on coronal magnetic resonance images revealed no differences in gross structures of the hippocampus between VPA-treated and control ferrets. BrdU-labeled cells were observed throughout the hippocampus of both two groups at PD 20. BrdU-labeled cells were immunopositive for Sox2 (>70%) and almost immunonegative for NeuN, S100 protein, and glial fibrillary acidic protein. BrdU-labeled Sox2-positive progenitors were abundant, particularly in the subgranular layer of the dentate gyrus (DG), and were denser in VPA-treated ferrets. When BrdU-labeled Sox2-positive progenitors were examined at 2 h after the second VPA administration on PD 7, their density in the granular/subgranular layer and hilus of the DG was significantly greater in VPA-treated ferrets compared to controls. The findings suggest that VPA exposure to ferret infants facilitates the proliferation of DG progenitors, supplying excessive progenitors for hippocampal adult neurogenesis to the subgranular layer.

SUBMITTER: Sawada K

PROVIDER: S-EPMC8505998 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionValproic acid (VPA) is an anticonvulsant/antiepileptic drug that regulates neurogenesis. Its effects vary depending on the timing of exposure and the types of neural progenitors involved. Neonatal exposure to VPA causes autism spectrum disorder-like behaviors in some mammalian species, including ferrets. Ferrets experience the cerebellar cortical histogenesis during early postnatal period. However, no studies have evaluated the effect of VPA on cerebellar corticohistogenesis. The present study aimed to determine the effects of VPA exposure on the developing cerebellar cortex in ferret kits with a particular focus on the cortical neurogenesis.MethodsThe experimental kits each received an intraperitoneal injection of VPA, 200 μg/g body weight, on postnatal days 6 and 7. EdU and BrdU were administered on postnatal days 5 and 7, respectively, to label cells proliferating prior to and following exposure to VPA.ResultsWe found that 2 h post BrdU injection, BrdU-labeled cells were abundantly distributed in the internal granular layer (IGL), whereas EdU-labeled cells were primarily relegated to the inner pre-migratory zone of the external granular layer (EGL). The density of BrdU-single-labeled cells was significantly lower in the EGL and significantly higher in the IGL of the VPA-exposed group, as compared to the control group. Immunostaining for doublecortin, a marker of immature neurons, was observed in BrdU-single-labeled cells in the IGL of the VPA-exposed group, which was significantly higher than that observed in the control group. EdU-single-labeled cells that had proliferated prior to VPA exposure were also detected in the IGL. While the cell density remained unchanged, significant changes were observed in the proportions of EdU-single-labeled cells immunostained with marker antigens; higher proportion of PCNA immunostaining, but lower proportion of S100 immunostaining in the VPA-exposed group compared to the control group.DiscussionThese findings suggest the presence of progenitors in the IGL of the developing cerebellar cortex in ferret kits. We called them "internal granular progenitors." The progenitors may proliferate in response to VPA, leading the differentiated lineage more toward neurons than to glial cells. Thus, VPA may facilitate the differentiative division of internal granular progenitors to produce cerebellar granular neurons.

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The Proliferation of Dentate Gyrus Progenitors in the Ferret Hippocampus by Neonatal Exposure to Valproic Acid.

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