Individual and Sex Differences in Behavior and Cortical Excitability in the Rat Valproate Model of Autism

Abstract

Highlights What are the main findings? Prenatal valproate treatment leads to increased excitability of the mPFC in male rats, and the strength of this effect is consistent with the degree of congenital malformations and behavioral deficits. In female offspring, significant and complex alterations develop in mPFC functions, despite lesser behavioral deficits compared to males. What are the implications of the main findings? In male offspring, malformations appear to be a good predictor of alterations in brain network functions. The relationship between cortical network alterations and behavior warrants further studies in female rats prenatally treated with valproate. Abstract The rodent prenatal valproate (VPA) treatment is a widely used animal model of idiopathic autism spectrum disorder (ASD). However, the presence of autistic-like symptoms is highly variable in treated offspring. The disruption of the excitation–inhibition balance of certain brain areas has been proposed as a main feature in both human ASD and the VPA model. The current study presents a detailed analysis of neural development, diverse behaviors, and neocortical excitability in a high number of individually identified VPA-treated rat offspring of both sexes. Neocortical excitability was assessed using electrophysiological and intrinsic optical imaging methods. Prenatal VPA treatment caused a delay in early postnatal sensorimotor development in rat pups of both sexes. Behavioral effects were associated with congenital morphological alterations (e.g., tail kink), as shown by stratification by principal component analysis and correlation analysis. Social deficits were evident only in the VPA-treated male offspring, while the females appear to be resistant to this effect. Prenatal VPA treatment was associated with sex- and region-dependent alterations in the excitability and seizure susceptibility of entorhinal and prefrontal cortical slices. Cortical excitability measures showed partial correlation with morphological and behavioral parameters. Thus, the current study further supports the validity of the rodent prenatal VPA model as a model of ASD for both sexes, but the variable degree of affectedness should be taken into account. Congenital malformation severity, including tail kink, may serve as a readily observable marker for subsequent physiological alterations, particularly in males.