Repetitive stereotyped 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 creation of habits and sequential behaviors; therefore, its dysregulation could promote autistic repetitive behaviors. Nevertheless, inspection of substantia nigra pars compacta (SNpc) DA neurons in ASD models has been overlooked and specific evidence of their altered activity in ASD and FXS is absent. Here, we show that hyperactivity of SNpc DA neurons is an early feature of FXS. The underlying mechanism relies on an interplay between metabotropic glutamate receptor 1 (mGluR1) and ErbB tyrosine kinases, receptors for the neurotrophic and differentiation factors known as neuregulins. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, concurrently rescued by ErbB inhibition. In conclusion, beyond providing the first evidence that nigral DA neuron hyperactivity is a signature of FXS and nigral mGluR1 and ErbB4/2 play a relevant role in FXS etiology, we demonstrate that inhibiting ErbB is a valuable pharmacological approach to attenuate stereotyped repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS treatment.

重复的刻板行为是自闭症谱系障碍 （ASD） 和脆性 X 综合征 （FXS） 的核心症状，脆性 X 综合征是智力障碍和自闭症的普遍遗传原因。黑质纹状体多巴胺 （DA） 回路控制习惯和顺序行为的运动和创造;因此，其失调可能会促进自闭症重复行为。然而，在 ASD 模型中对黑质致密部 （SNpc） DA 神经元的检查被忽视了，并且不存在它们在 ASD 和 FXS 中活性改变的具体证据。在这里，我们表明 SNpc DA 神经元的多活度是 FXS 的早期特征。潜在机制依赖于代谢型谷氨酸受体 1 （mGluR1） 和 ErbB 酪氨酸激酶之间的相互作用，ErbB 酪氨酸激酶是神经营养因子和分化因子的受体，称为神经调节蛋白。黑质 DA 神经元中 ErbB4 和 ErbB2 的上调驱动 FXS 小鼠的神经元多动和重复行为，同时受到 ErbB 抑制的拯救。总之，除了提供第一个证据证明黑质 DA 神经元多动是 FXS 的特征并且黑质 mGluR1 和 ErbB4/2 在 FXS 病因中起相关作用之外，我们还证明抑制 ErbB 是一种有价值的药理学方法，可以减轻刻板的重复行为，从而为 ASD 和 FXS 治疗的创新疗法开辟一条途径。