The increase of cortical volume in the early stage of a valproic acid model of autism may be due to a compensatory mechanism

Abstract Background & Aim: Studies have found brain enlargement in early autism. However, it is not clear which brain regions are enlarged and the mechanism of the enlargement. In this study, we established an autism model and used magnetic resonance imaging (MRI) to determine whether brain volume was increased in the early stages of autism and to explore its underlying mechanism. Methods The autism model was established by prenatal exposure to valproic acid (VPA) in pregnant rats. At the age of 4 weeks, the offspring rats were identified by using the three-chamber social interaction test, open field test and self-grooming test. T2-weighted images of all subjects were obtained, and the cortex volume of the region of interest(ROI) was automatically extracted and measured, and correlated with the autism-like behaviors. The GAD67 expression was tested by western blot and immunofluorescence, and its correlation with the brain volume was analyzed. Results Behavioral tests confirmed the success of the autism model establishment in offspring rats. MRI showed that the volume of prefrontal cortex (PFC) and temporal cortex (TC) increased significantly in VPA rats than in healthy control (HC) group (p < 0.05). In VPA group, The TC volume was negatively correlated with the communication time between the tested rats and the stranger (r=-0.82, P = 0.01). The PFC volume was negatively correlated with the times that the tested rats crossed all lines in the open field (r=-0.87, P = 0.005), and positively correlated with the grooming time (r = 0.83, P = 0.01).Western blotting and immunofluorescence showed that the expression of GAD67 in the HC, PFC and TC in VPA group decreased significantly (P < 0.05).The expression level of GAD67 was negatively correlated with the volume of HC (r=-0.79, p = 0.02), PFC (r=-0.72, P = 0.04) and TC (r=-0.72, P = 0.04) respectively. Conclusion The volume of some brain regions increased in the early stage of VPA rats, which was similar to that of human autism. The enlargement of some brain regions in early autism may be due to a compensatory mechanism, in which the brain volume increases to amend the imbalance of the excitement-inhibition system.