Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorders

The key pathological mechanisms underlying autism spectrum disorders (ASDs) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders, however it is unclear whether this dysfunction drives ASDs or is an adaptation to the altered brain microenvironment. To determine this, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in a series of preclinical models of monogenic ASDs. These models were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. However, all models displayed a common trait of hyperexcitability. We determined that SV fusion events and SV cargo trafficking were unaffected in all models investigated. However, a key convergent phenotype was revealed, a depression in activity-dependent bulk endocytosis (ADBE). This suggests that the depression in ADBE is a homeostatic mechanism to correct hyperexcitability in the ASD brain.