| Autism Spectrum Disorder (ASD), a neurodevelopmental disorder, is thought to originate
from excess connectivity in the brain, potentially due to inadequate pruning of neurons.
Microglia, the primary immune cells of the central nervous system (CNS), play a crucial role
in pruning excess dendrites and synapses during early brain development. Valproic Acid (VPA),
commonly used to treat epilepsy, bipolar disorder, and migraines, is a histone deacetylase
inhibitor with known teratogenic effects and is associated with a high risk of autism. Extensive
animal studies have investigated the behavioral, and neuronal aspects of VPA, including
hyperconnectivity, but the state of microglia in early development remains poorly understood.
Previous research in our lab demonstrated that valproic acid reduces microglial numbers
during neonatal development. However, the mechanism behind this reduction was not
explored. In the present study, we investigated the mechanism underlying the decrease in
microglial cell counts following prenatal VPA exposure. Our results show VPA significantly
increased apoptosis at embryonic day 14 (E14), embryonic day 17 (E17), and postnatal day 1
(PD1), primarily outside the microglia, along with a reduced brain weight at E14 followed by an
increase in brain weight at PD1. In addition, given the potential immunomodulatory effects of
VPA, we also measured the transcript levels of the pro-inflammatory cytokines TNF-α, IL-6,
IL-1β, and NOS2 to assess VPAs impact. The results showed no significant difference between
the groups. Microglia seem more resilient to the effect of the insult in embryonic life than neural
precursor cells, which seem more susceptible to VPA.
Keywords: [Valproic acid], [Autism spectrum disorder], [Microglia], [Cell death], [Brain
development], [VPA mouse model of autism] |