Retinal cell mosaics in the valproate-induced rat model of autism spectrum disorder

Valproic acid (VPA) is a widely used antiepileptic drug that also increases the risk of neurodevelopmental disorders in the offspring of exposed mothers. Prenatal exposure to VPA is a widely used rodent model of autism spectrum disorder (ASD). Anatomical, functional and molecular alterations in the retinas of various ASD model animals have been described, but the impact on the neural composition of the retina remains unclear. We examined whether the density and spatial regularity of selected retinal neuron populations are altered in the VPA induced model of ASD. Whole-mount retinas of 2-month-old VPA-treated and control animals were immunolabeled for S-cones, horizontal cells, AII amacrine cells, and parvalbumin-positive wide-field amacrine cells (PV-wfACs), and the positions of labelled cells mapped in various regions of interest across the retina. Multivariate analysis of the densities of the four cell types was used to identify latent factors accounting for their covariance structure. The first principal component was identified as a measure of retinal centrality and used to adjust for retinal location when testing for treatment effects. Linear mixed-effects modeling revealed a 9% decrease in AII amacrine cell density and a 12% increase in PV-wfACs density in VPA-model animals. Regularity indices calculated from nearest neighbor distances or Voronoi-domain areas of cell mosaics were largely unchanged. These findings suggest that prenatal VPA exposure selectively alters the cellular composition of inhibitory inner retinal circuitry in the rat ASD model, while leaving the self-organizing mechanisms responsible for retinal spatial order largely intact.