Dopamine modulates the retinal clock through melanopsin-dependent regulation of cholinergic waves during development

The mammalian retina contains an autonomous circadian clock that controls various aspects of retinal physiology and function, including dopamine (DA) release by amacrine cells. This neurotransmitter plays a critical role in retina development, visual signalling, and phase resetting of the retinal clock in adulthood. Interestingly, bidirectional regulation between dopaminergic cells and melanopsin-expressing retinal ganglion cells has been demonstrated in the adult and during development. Additionally, the adult melanopsin knockout mouse (Opn4 ^-/-) exhibits a shortening of the endogenous period of the retinal clock. However, whether DA and / or melanopsin influence the retinal clock mechanism during its maturation is still unknown.

Using wild-type Per2 ^Luc and melanopsin knockout (Opn4 ^-/-::Per2 ^Luc) mice at different postnatal stages, we found that the retina generates self-sustained circadian rhythms from postnatal day 5 in both genotypes and that the ability to express these rhythms emerges in the absence of external time cues. Intriguingly, only in wild-type explants, DA supplementation lengthened the endogenous period of the clock during the first week of postnatal development through both D1- and D2-like dopaminergic receptors. Furthermore, the blockade of spontaneous cholinergic retinal waves, which drive DA release in the early developmental stages, shortened the period and reduced the light-induced phase shift of the retinal clock only in wild-type retinas.

These data suggest that DA modulates the molecular core of the clock through melanopsin-dependent regulation of acetylcholine retinal waves, thus offering an unprecedented role of DA and melanopsin in the endogenous functioning and the light response of the retinal clock during development.