A novel developmental role for dopaminergic signaling to specify hypothalamic neurotransmitter identity

Hypothalamic neurons expressing histamine and orexin/ hypocretin (hcrt) are necessary for normal regulation of wakefulness. In Parkinsons disease the loss of dopaminergic neurons is associated with elevated histamine levels and disrupted sleep/wake cycles, but the mechanism is not understood. To characterize the role of dopamine in development of histamine neurons, we inhibited the translation of the two non-allelic forms of tyrosine hydroxylase (th1 and th2) in zebrafish larvae. We found that dopamine levels were reduced in both th1 and th2 knockdown, but serotonin level and number of serotonin neurons remained unchanged. Further, we demonstrate that th2 knockdown increased histamine neuron number and histamine levels, while increased dopaminergic signaling using the dopamine precursor L-DOPA or dopamine receptor agonists reduced the number of histaminergic neurons. Increases in the number of histaminergic neurons were paralleled by matching increases in the numbers of hcrt neurons, supporting observations that histamine regulates hcrt neuron development. Finally, we show that histaminergic neurons surround th2-expressing neurons in the hypothalamus, and we suggest that dopamine regulates terminal differentiation of histamine neurons via paracrine actions or direct synaptic neurotransmission. These results reveal a role for dopaminergic signaling in regulation of neurotransmitter identity and a potential mechanism contributing to sleep disturbances in Parkinson's disease.