Molecular autism · 2025
Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder.
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Bonnycastle Katherine, Nawaz Mohammed Sarfaraz, Kind Peter C, Cousin Michael A
Аннотация
BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) 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 ASD or is an adaptation to the altered brain microenvironment.
METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1+/-, Nlgn3-/y, Syngap+/-, Syngap+/Δ-GAP, Pten+/-) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran.
RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis.
LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression.
CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons.
METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1+/-, Nlgn3-/y, Syngap+/-, Syngap+/Δ-GAP, Pten+/-) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran.
RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis.
LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression.
CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons.