ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome
Repetitive behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and habit formation; therefore, its dysregulation stands as a leading substrate for repetitive behaviors. However, beyond indirect evidence, specific assessment of nigral DA neuron activity in ASD and FXS models is lacking. Here, we show that hyperactivity of substantia nigra pars compacta (SNpc) DA neurons is an early feature of FXS. The underlying mechanisms rely on mGluR1 and ErbB receptors. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, simultaneously rescued by ErbB inhibition. In conclusion, beyond providing the first evidence of dysregulation of the SNpc DA nucleus in FXS, we identify novel targets - ErbB receptors - whose inhibition proficiently attenuates repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS.