Zdhhc17/Hip14 functions in neurons to control behavior via DHHC-dependent and independent mechanisms

To navigate a complex sensory environment, animals filter out inconsequential sensory inputs and habituate to familiar stimuli. By establishing innate response thresholds and modifying them through habituation, animals can focus on key sensory stimuli while ignoring irrelevant ones. Huntingtin-interacting protein 14 (Hip14), also known as zDHHC17, is a palmitoyl acyltransferase (PAT) that regulates both of these sensory filtering processes. Larval zebrafish lacking Hip14 are hypersensitive to acoustic stimuli and cannot regulate their responses to repeated acoustic stimuli via habituation. Yet how Hip14 regulates these behaviors, and whether it does so through different mechanisms, is unknown. Prior work demonstrates that Hip14 is expressed throughout the nervous system, but where it functions to control these overlapping sensory functions remains unaddressed. We found that the catalytic (DHHC) domain, despite being a defining feature for PATs including Hip14, is not required for regulating acoustic startle sensitivity, but is sufficient to regulate habituation. We find, furthermore, that Hip14 function in either mechanosensory hair cells or neurons can restore normal startle sensitivity, whereas habituation is regulated exclusively by neuronal expression. Finally, we found that the Hip14 N-terminal ankyrin repeat domains are crucial for its control of behavior. Together, our study establishes that habituation and startle sensitivity are regulated through distinct circuit and molecular mechanisms and establishes a new in vivo catalytic-independent role for Hip14.