Transient Dysregulation of Dopamine Signaling in a Developing Drosophila Arousal Circuit Permanently Impairs Behavioral Responsiveness in Adults

The dopamine ontogeny hypothesis for schizophrenia proposes that transient dysregulation of the dopaminergic system during brain development increases the likelihood of this disorder in adulthood. To test this hypothesis in a high-throughput animal model, we have transiently manipulated dopamine signaling in the developing fruit fly Drosophila melanogaster and examined behavioral responsiveness in adult flies. We found that either a transient increase of dopamine neuron activity or a transient decrease of dopamine receptor expression during fly brain development permanently impairs behavioral responsiveness in adults. A screen for impaired responsiveness revealed sleep-promoting neurons in the central brain as likely postsynaptic dopamine targets modulating these behavioral effects. Transient dopamine receptor knockdown during development in a restricted set of ~20 sleep-promoting neurons recapitulated the dopamine ontogeny phenotype, by permanently reducing responsiveness in adult animals. This suggests that disorders involving impaired behavioral responsiveness might result from defective ontogeny of sleep/wake circuits.