The Effect of Valproic Acid Exposure throughout Development on Microglia Number in the Prefrontal Cortex, Hippocampus and Cerebellum

• Published in: Neuroscience 2022-01, Vol.481, p.166-177
• Main Authors: Gifford, Janace J., Deshpande, Pooja, Mehta, Priyanka, Wagner, George C., Kusnecov, Alexander W.
• Format: Article
• Language: English
• Subjects: Animals; autism; Behavior, Animal - physiology; Cerebellum - pathology; development; Hippocampus; Mice; Mice, Inbred C57BL; microglia; Microglia - pathology; Prefrontal Cortex; Prenatal Exposure Delayed Effects - pathology; valproic acid; Valproic Acid - toxicity
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2021.11.012

•Microglia follow a unique developmental trajectory differing across brain areas.•Valproic acid exposure during early life results in alterations to microglia number.•Results support studying neuroinflammation in the etiology of a number of disorders. Microglia serve as resident immune cells in the brain, responding to insults and pathological developments. They have also been implicated in shaping synaptic development and regulation. The present study examined microglial cell density in a number of brain regions across select postnatal (P) ages along with the effects of valproic acid (VPA) on microglia density. Specifically, C57BL/6JCx3CR1+/GFP mice were examined for microglial cell number changes on P7, P14, P30, and P60 under baseline conditions and following 400 mg/kg VPA or saline. The prefrontal cortex (PFC), hippocampus and cerebellum were observed. Under control conditions, the results showed a shift in the number of microglia in these brain areas throughout development with a peak density in the hippocampus at P14 and an increase in PFC microglial numbers from P15 to P30. Interestingly, VPA treatment enhanced microglial numbers in a region-specific manner. VPA at P7 increased microglial cell number in the hippocampus and cerebellum whereas P14 VPA treatment altered microglial density in the cerebellum only. Cerebellar increases also occurred after VPA at P30, and were attended by an effect of increased numbers in the PFC. Finally, animals treated with VPA at P60 exhibited decreased microglia density in the hippocampus only. These results suggest rapid VPA-induced increases in microglial cell density in a developmentally-regulated fashion which differs across distinct brain areas. Furthermore, in the context of prior reports that early VPA causes excitotoxic damage, the present findings suggest early VPA exposure may provide a model for studying altered microglial responses to early toxicant challenge.