Research on Autism Spectrum Disorder and Its Comorbidities:Pathological Mechanisms and Therapeutic Targets

摘要

Autism Spectrum Disorder(ASD) is a neurodevelopmental disorder characterized by two core symptoms: social deficits and repetitive behaviors, with currently no effective diagnostic or therapeutic approaches available. Notably, beyond the core symptoms, individuals with ASD frequently present with comorbid conditions such as anxiety disorders, epilepsy, and sensory deficits. The co-occurrence of ASD and comorbidities not only complicates diagnosis and treatment but also poses considerable challenges to understanding the underlying pathological mechanisms. Therefore, further investigation into the mechanisms of ASD and its comorbidities is of significant clinical importance and may offer new insights for ASD diagnosis and intervention. To address this, we employed a combination of in vivo and in vitro strategies, including high-throughput transcriptomic profiling, multiphoton calcium imaging, multichannel in vivo electrophysiology, and viral-mediated genetic manipulation. Our research on ASD and its comorbidities has revealed the following key findings:(1) Transmembrane protein 74(Tmem74) was identified as a key regulator of ASD comorbid with anxiety, with the prelimbic cortex(PL) serving as a critical brain region. At the circuit level, we demonstrated that two spatially distinct populations of PL pyramidal neurons project to the striatum(STR) and basolateral amygdala(BLA), respectively, modulating ASD-related and anxiety-related behaviors;(2) Beyond anxiety, we also found disrupted neural circuits in the medial prefrontal cortex(mPFC) in ASD comorbid with sensory deficits, and identified hippocampal circuit dysfunction as a primary driver of ASD comorbid with epilepsy. In summary, our work elucidates the complex interplay between ASD and its comorbidities at both molecular and circuit levels, highlighting potential therapeutic strategies targeting risk genes and dysregulated neural circuits.