Motor Coordination Deficits and Developmental Expression of GABAA Receptor Subunits (α1, α2 and β1) and GAD67 in the Cerebellum of Mice Prenatally Exposed to Valproic Acid

Abstract

Background: The cerebellum integrates sensory information to maintain balance and posture, allowing movement guidance. Perinatal damage to this brain region correlates with an increased incidence of Autism Spectrum Disorder (ASD), a major neurodevelopmental condition where poor motor performance in eye–hand coordination, balance and gait is observed. The cerebellum of ASD individuals is affected by reduced GABAergic signaling that leads to an excitatory/inhibitory imbalance. Methods: Motor coordination behavior were tested and Western blot essays performed to study the developmental expression of GABAergic signaling proteins, namely GABAA receptor (α1, α2 and β1) subunits and glutamate decarboxylase 67 (GAD67), in CD1 mice prenatally exposed to valproic acid (VPA), a preclinical model of ASD. Results: The VPA group exhibited motor coordination deficits on postnatal day 30 (P30) compared to the control. The expression profiles for the control group revealed that GABAA-α1 increased linearly, while GABAA-β1 displayed the opposite pattern and GABAA-α2 presented one peak of expression (P8). GAD67 decreased from embryonic day 16 (E16) to P8 but increased linearly after the first week of postnatal development (P8-P30). The developmental expression profile for all these proteins was disrupted by prenatal exposure to VPA. Conclusions: Motor coordination deficits correlate with a downregulated expression of GABAA (α1, α2 and β1) subunits and GAD67 through cerebellar development in individuals that were prenatally exposed to VPA.