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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.
Highlights
Valproic acid (VPA), a well-known antiepileptic/anticonvulsant drug, acts as an inhibitor of histone deacetylases 1 and 2 (Göttlicher et al, 2001; Phiel et al, 2001)
Coronal magnetic resonance (MR) images of the hippocampus of VPAtreated ferrets and controls are shown in two identical planes, that is, the plane including the caudal end of the splenium of the corpus callosum (Figure 1B) and in the plane including the posterior commissure (Figure 1C)
A connection from the dorsal to ventral hippocampus was found in coronal MR images at the posterior commissure in VPAtreated and control ferrets (Figure 1C)
Summary
Valproic acid (VPA), a well-known antiepileptic/anticonvulsant drug, acts as an inhibitor of histone deacetylases 1 and 2 (Göttlicher et al, 2001; Phiel et al, 2001). Prenatal and neonatal VPA exposure can alter the development of other brain regions, such as the hippocampus (Edalatmanesh et al, 2013; Juliandi et al, 2015; Wang et al, 2016; Hou et al, 2018; Win-Shwe et al, 2018), cerebellum (Hou et al, 2018; Mirza and Sharma, 2019), and amygdala (Olexová et al, 2016; Wang et al, 2016) In association with such VAP-induced brain abnormalities, VPA regulates neurogenesis; studies have reported inconsistent findings – facilitation of neuronal differentiation of rat adult hippocampal neuronal progenitors (Hsieh et al, 2004) and mouse embryonic stem cells (Juliandi et al, 2012) but inhibition of neuronal differentiation of cortical progenitors in mouse fetuses (Fujimura et al, 2016). We examined gross structural and histological changes in the hippocampus and tracked proliferative cells by BrdU labeling following VPA administration to ferret infants on postnatal days (PDs) 6 and 7
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