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

Abstract

Animals 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-associated ap2s1 critically supports habituation learning in acoustically-evoked escape behavior of zebrafish. ap2s1 encodes 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 domains and subunits of the AP2 complex regulate acoustically-evoked behavior selection and habituation learning. Furthermore, ap2s1 biases 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, identifying at least three spatially and 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 of ap2s1 in human conditions including autism spectrum disorder.SIGNIFICANCE STATEMENTThe AP2S1 gene 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 which ap2s1 modulates behavior. We find that ap2s1 regulates simple acoustically-evoked learning, as well as how individuals bias behavioral choice in a wide variety of contexts. We show that ap2s1 acts 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.

Integration of cooperative and opposing molecular programs drives learning-associated behavioral plasticity

“…Moreover, our data are consistent with a model in which our pharmacogenetic perturbations lead to broad impacts on brain activity. Finally, these data are consistent with the reported hypersensitivity of all of the tested mutants to low-intensity stimuli [ 25 , 28 , 29 , 33 ], which suggest baseline deficits in the thresholding of acoustic stimuli. Importantly, although habituation deficits may co-occur with changes in response thresholds as they do in these mutants, these deficits may also occur independently [ 25 , 42 ], suggesting that they are mechanistically separable.…”

“…We recently identified a splice site mutation in the adaptor related protein complex 2 subunit sigma 1 ( ap2s1 ) gene, positioning the AP-2 adaptor complex as a fifth genetic regulator of habituation learning. We previously demonstrated that besides its role in habituation learning, AP-2 modulates sensorimotor decision-making via the Calcium-Sensing Receptor, CaSR [ 27 , 33 ]. Yet whether AP-2 also modulates NMDA, dopamine, or glycinergic signaling to regulate habituation learning has not been examined.…”