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 in the literature, but the impact on the neural composition of the retina remains unclear. We examined whether and how the density and spatial regularity of selected retinal neurons 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 amacrines (PV-wfACs), and the positions of labelled cells mapped in various regions of interest (n = 39 for treated, n = 32 for control animals) across the retinas. Multivariate analysis of variance revealed a significant overall effect of VPA on cell densities (p = 6.1x10-7, 2 = 0.43), driven mainly by reduced AII amacrine density, while horizontal cells showed a modest reduction and S-cones were unaffected. After adjusting for retinal location, analysis of covariance indicated a 7% decrease in AII cells and a 15% increase in PV-wfACs. 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 inhibitory inner retinal circuitry in the rat ASD model at the time of cell differentiation, but self-organizing mechanisms responsible for spatial order are not affected. Lay SummaryValproic acid (VPA) is a medicine for epilepsy, but it can also raise the risk of autism in children when taken during pregnancy. In rats exposed to VPA before birth, we found changes in certain nerve cells of the retina: one type of cell important for night vision was reduced, while another type increased slightly, while most other cells stayed the same. This suggests that the changes in development that lead to autism may also be reflected in the structure and function of the eye.