Maternal Exposure to Valproic Acid Primarily Targets Interneurons Followed by Late Effects on Neurogenesis in the Hippocampal Dentate Gyrus in Rat Offspring

Abstract

Valproic acid (VPA) is used to establish models of experimental autism. The present study investigated the developmental exposure effect of VPA on postnatal hippocampal neurogenesis in accordance with the exposure scheme of OECD Test Guideline 426 adopted for developmental neurotoxicity. Pregnant rats were administered drinking water containing 0, 667, or 2000 ppm VPA from gestational day 6 until day 21 post-delivery. In the subgranular zone (SGZ) and granule cell layer (GCL) of offspring, the number of granule cell lineage subpopulations remained unchanged upon weaning. However, in the hilus of the dentate gyrus, the number of reelin interneurons decreased at ≥667 ppm, and the number of PVALB or GAD67 interneurons decreased at 2000 ppm. Conversely, Reln and Gad1 transcript levels increased at 2000 ppm, but Pvalb and Grin2d decreased, in the dentate gyrus. At the adult stage, PCNA proliferating SGZ cells, NeuN postmitotic SGZ/GCL neurons, and ARC or COX2 GCL neurons increased at ≥667 ppm. In the dentate hilus, decreases in GAD67 interneuron subpopulations and Grin2d transcript levels sustained at 2000 ppm. These results suggested that VPA primarily targets interneurons by developmental exposure, and this is followed by late effects on granule cell lineages, likely by influencing SGZ cell proliferation and synaptic plasticity. A reduced population of reelin or PVALB interneurons did not affect distribution of granule cell lineage subpopulations upon weaning. The late effect on neurogenesis, which resulted in increased GCL neurons, might be the result of a sustained decrease in GAD67 interneurons expressing NR2D encoded by Grin2d.

Autism spectrum disorder: neuropathology and animal models

“…Cell density is increased in the hippocampus [94], but it is decreased in the cerebellum [164] and the superior olivary nuclei of the brainstem [221] following prenatal VPA exposure. VPA exposure in utero leads to fewer parvalbumin-expressing interneurons in the parietal and occipital cortex [127], fewer glutamate decarboxylase 67-immunoreactive interneurons in the dentate gyrus, in the cerebellum and in the cortex [374], and loss of motor neurons in some of the motor nerve nuclei in the brainstem [303]. …”

A Developmental Study of Abnormal Behaviors and Altered GABAergic Signaling in the VPA-Treated Rat Model of Autism

“…Although many studies have investigated the role of GABAergic signaling in rodent neural development and behaviors relevant to autism (Tabuchi et al, 2007 ; Cusmano and Mong, 2014 ; Lauber et al, 2016 ; Olexová et al, 2016 ; Wei et al, 2016 ; Chau et al, 2017 ; Watanabe et al, 2017 ), the behavioral ontogeny as determined by changes in GABAergic system of different brain regions is poorly characterized. Here, we employed a VPA rat model of autism to investigate the autism-like behaviors and GABAergic GAD67 expression underlying these altered behaviors in multiple brain areas at the developmental stages from birth to adulthood.…”

Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats

“…Therefore, Vgf and Dpysl4 downregulation may suppress synaptic plasticity in the hippocampal dentate gyrus. However, we have previously revealed that VPA exposure increased ARC or cyclooxygenase 2‐mediated synaptic plasticity as a late effect at the adult stage (Table 1; Watanabe et al, 2017). Although we did not examine microRNA expression, microRNA‐mediated homeostatic synaptic plasticity can be induced as a compensatory response to alterations in neuronal activity (Hou et al, 2015).…”

“…We have previously found that maternal exposure to PTU, an antithyroid agent that causes hypothyroidism (Shibutani et al, 2009), had diverse effects on hippocampal neurogenesis including aberrations in granule cell lineages, GABAergic interneurons, and synaptic plasticity in rat offspring and that the disruption was mostly sustained through the adult stage on PND 77 (Table 1; Shiraki et al, 2016). However, VPA only affected interneuron subpopulations at the end of maternal exposure and typically showed a late effect on granule cell lineages involving synaptic plasticity at the adult stage (Table 1; Watanabe et al, 2017). GLY had a reversible effect on granule cell lineages at the end of maternal exposure and a sustained effect on interneuron subpopulations (Table 1; Akane, Shiraki et al, 2013).…”

“…426: Developmental Neurotoxicity Study; OECD, 2007) in rodent animals (Shibutani, 2015). Importantly, some neurotoxicants, such as manganese, aluminum, 6‐propyl‐2‐thiouracil (PTU), glycidol (GLY), and valproic acid (VPA), had a sustained or late effect on neurogenesis in terms of granule cell lineage subpopulations, interneuron subpopulations, and/or other regulatory systems (Wang et al, 2012; Akane, Shiraki et al, 2013; Shiraki et al, 2016; Watanabe et al, 2017; Inohana et al, 2018). If the effect on neurogenesis is permanent in nature, the concern arises regarding learning and memory formation later in life.…”