The Adaptor Protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows

Abstract

ABSTRACTAnimals constantly perceive and integrate information across sensory modalities, and their nervous systems must select behavioral responses appropriate to the current situation and prior experience. Genetic factors supporting this behavioral flexibility are often disrupted in neuropsychiatric conditions, and our previous work revealed the disease-associatedap2s1gene critically supports habituation learning in acoustically-evoked escape behavior of zebrafish.ap2s1encodes a subunit of the AP2 endocytosis adaptor complex and has been linked to autism spectrum disorder, though its mechanism and direct behavioral importance have not been established. Here, we show that multiple subunits of the AP2 complex regulate acoustically-evoked behavior selection and habituation learning. Furthermore,ap2s1biases the choice between distinct escape behaviors in sensory modality-specific manners, and more broadly regulates action selection across different sensory contexts. Using tissue-specific and inducible transgenic rescue, we demonstrate that the AP2 complex functions acutely and in the nervous system to modulate acoustically-evoked habituation learning, suggesting several spatially and/or temporally distinct mechanisms through which AP2 regulates different aspects of escape behavior selection and performance. Altogether, we demonstrate that the AP2 complex coordinates action selection across stimulus modalities and contexts, providing a new vertebrate model for the role ofap2s1in human conditions including autism spectrum disorder.SIGNIFICANCE STATEMENTTheAP2S1gene has been linked to learning disabilities and autism spectrum disorders (ASD), though the mechanisms underlying its impact on human behavior are unknown. We explored how, when, and where this gene regulates vertebrate behavior, developing a zebrafish model to identify the roles and mechanisms through whichap2s1modulates behavior. We find thatap2s1regulates simple acoustically-evoked learning, as well as how individuals bias behavioral choice in a wide variety of contexts. We show thatap2s1acts at multiple distinct time periods and locations both within and outside of neuronal tissues, revealing the diverse mechanisms and pathways through which it modulates vertebrate behavior.