Spironolactone Partially Reverses Autism-Like Behaviors Linked to ErbB4 and mTOR Phosphorylation in the Mouse Prefrontal Cortex and Striatum

Abstract

Background and Aims

Autism spectrum disorder (ASD) is a condition resulting from a combination of genetic and environmental influences that lead to atypical brain development, particularly in regions such as the striatum and prefrontal cortex. There is increasing evidence linking the epidermal growth factor (EGF) and its receptor (EGFR or ErbB1) to the etiopathogenesis of ASD. However, ErbB4, another ErbB member, has also been implicated in this process. To investigate whether dysregulation of ErbB4 and its downstream mTOR signaling pathway in the striatum and prefrontal cortex contributes to stereotypical behaviors and social deficits in an autism-like rodent model.

Methods

We analyzed the phosphorylation levels of ErbB4and mTOR in the prefrontal cortex and striatum of 31 d old mice that were prenatally exposed to valproate (VPA; 500 mg/kg) or the control vehicle (0.9 % NaCl). Social and stereotypic behaviors were assessed using the three-chamber social test and the marble burying test, respectively. Then, the VPA groups were treated with 50 mg/kg of spironolactone, a selective ErbB4 antagonist.

Results

Prenatal exposure to VPA induced deficits in social interaction and an increase in repetitive behaviors. These behaviors coexist with dysregulation of the ErbB4 phosphorylation and modifications in the mTOR signaling pathway in both brain regions. Treatment with spironolactone reduced repetitive behaviors, which was consistent with reduced ErbB4 phosphorylation and mTOR signaling.

Conclusions

These results support the idea that ErbB4 has abnormal expression and activity levels in the striatum and prefrontal cortex. Antagonizing ErbB4 with spironolactone improves repetitive behavioral patterns associated with ASD.