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Kwoon Y Wong, DiJon D. Hill, Weston Pack; Melatonin modulates M4-type intrinsically photosensitive retinal ganglion cells (ipRGCs). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5564.
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© ARVO (1962-2015); The Authors (2016-present)
In the retina, the hormone melatonin is secreted at night by photoreceptors and serves as a dark-adaptive signal. Melatonin receptors have been found in many types of retinal neurons including ipRGCs (Sengupta et al. PLoS One 2011), suggesting it may modulate the physiology of ipRGCs. Here, we tested this possibility.
Eyecups were harvested from dark-adapted Sprague Dawley rats and superfused by Ames’ medium. Whole-cell current-clamp recording was made from M4-type ipRGCs which could be identified by their enormous somas. All stimuli were full-field 480nm light. In the experiments examining rod/cone-driven photoresponses, low-intensity stimuli too dim to activate melanopsin were used. In the experiments that studied melanopsin-based light responses, rod/cone input was blocked using the glutamate analogs L-AP4, DNQX and D-AP5, and stimulus intensities suprathreshold for melanopsin activation were used.
The rod/cone-driven light response of M4 cells consisted of a rapid, sustained depolarization accompanied by an increase in spike rate. Bath application of melatonin (10 nM) during subjective day increased both the duration and amplitude of this depolarization. Paradoxically, it attenuated the light-evoked increase in spiking. These effects persisted when melatonin was added in the presence of dopamine receptor antagonists (5 µM SCH23390 + 5 µM spiperone) but were abolished when it was applied in the presence of the melatonin receptor antagonist luzindole (2 µM). Luzindole added to normal Ames during subjective night had the opposite effects on rod/cone-driven photoresponses: the duration of the depolarization was reduced while the spiking increase was enhanced. It also decreased the amplitude of the depolarization although this effect was not statistically significant (p=0.175). In the presence of rod/cone-signaling blockers, M4 cells generated sluggish, melanopsin-based depolarizing light responses, which were not affected by the addition of melatonin.
Endogenous melatonin modulates the rod/cone-mediated photoresponses of M4 cells. Melatonin is known to inhibit dopamine release from amacrine cells (Dubocovich Nature 1983) although such inhibition is not required for the effects observed here. Melatonin does not appear to act directly on M4 cells because its effects were abolished by rod/cone blockade. Instead, it probably acts on M4 cells’ presynaptic circuits.
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