Roles of the Neuregulin 1/ErbB4 Signaling Pathway in the Pathogenesis of Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that first manifests in the early stages of childhood. The exact underlying mechanism of ASD remains unknown, and its etiology is rather complex. Neuronal migration, cognitive development, and continuous neural plasticity are strongly influenced by the Neuregulin 1 (NRG1)/ErbB4 signaling pathway. Hence, the pathogenesis of ASD may be closely connected to dysfunction of the NRG1/ErbB4 pathway. According to our current review, either the activation or inhibition of this pathway can lead to the development of ASD, and GABAergic system dysfunction can result in ASD-like behaviors. Moreover, NRG1 binds to ErbB to promote GABA release, and abnormal NRG1 activity affects GABAergic neuron development and function, thus impairing cognition and social interactions. Additionally, the activity of the PI3K/AKT/mTOR pathway differs in various brain regions, and its activation or inhibition can lead to the development of ASD. By activating ErbB CTY-1, NRG1 promotes the development of neurodevelopmental disorders through further activation of the PI3K/AKT/mTOR pathway. Therefore, the NRG1/ErbB4 pathway can regulate GABAergic system functions and affect the activity of the PI3K/AKT/mTOR pathway, thereby resulting in abnormal social interactions and cognitive impairment. Targeting dysfunctions of the GABAergic system, the PI3K/AKT/mTOR pathway, and the NRG1/ErbB4 pathway are currently promising strategies for the treatment of ASD. Candidate agents that modulate these pathways have been shown to be effective in preclinical animal models. However, the limitations of these models and the considerable etiologic and phenotypic heterogeneity among patients with ASD continue to hinder their clinical translation. This article reviews evidence suggesting that the pathogenesis of ASD is closely associated with the NRG1/ErbB4 signaling pathway, the GABAergic system, and the PI3K/AKT/mTOR pathway. This article also analyzes the main obstacles to pharmacological interventions and provides a theoretical basis for understanding the pathogenesis of ASD and for identifying potential targets for future therapeutic strategies.