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Kwoon Wong; Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) Depend on the Retinal Pigment Epithelium (RPE) to Regenerate Melanopsin. Invest. Ophthalmol. Vis. Sci. 2013;54(15):400.
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© ARVO (1962-2015); The Authors (2016-present)
After light exposure, outer retinal photoreceptors depend partly on the RPE’s retinoid cycle to regenerate photoexcitable visual pigments. By contrast, ipRGCs are far from the RPE and thus have been hypothesized to regenerate photopigments (melanopsin) in a self-sufficient manner. Two previous studies (Doyle et al. 2006 PNAS; Tu et al. 2006 PNAS) were consistent with this hypothesis, although they only examined relatively brief or low-intensity light stimuli. Here, I tested the possibility that melanopsin regeneration depends on the RPE for higher-intensity and longer stimuli.
Multielectrode-array (MEA) spike recordings were made from either RPE-attached or isolated (i.e. RPE-less) retinas harvested from Long-Evans rats. The Ringer contained synaptic blockers to isolate melanopsin-based light responses. Full-field 480-nm light was presented to each piece of retina from underneath the MEA for 1 hr.
At all light intensities tested (12.8 log, 13.7 log and 14.6 log quanta cm-2 s-1), ipRGCs in RPE-attached retinas generated tonic melanopsin photoresponses that lasted throughout the 1-hr light step. For ipRGCs in isolated retinas, melanopsin photoresponses were tonic at 12.8 log quanta, somewhat more transient at 13.7 log quanta, and very transient at 14.6 log quanta with responses lasting only ~10 min. Long-lasting light responses returned when isolated retinas were incubated in exogenous 9-cis-retinal. When RPE-attached retinas were treated with inhibitors of the RPE’s retinoid cycle (13-cis-retinoic acid and α-phenyl-N-tert-butylnitrone) or a chemical that specifically damages Müller cells (DL-2-aminoadipic acid), melanopsin photoresponses to the 14.6 log stimulus became very transient and lasted for only ~10 min.
IpRGCs can regenerate melanopsin self-sufficiently during exposure to moderate-intensity light, possibly through photoreversal, i.e. melanopsin retains all-trans-retinal after photoexcitation and absorption of a subsequent photon isomerizes this retinoid to 11-cis-retinal (Mure et al. 2007 J. Biol. Rhythms). However, the RPE’s retinoid cycle becomes important when ipRGCs are strongly activated by prolonged stimuli exceeding ~14 log quanta cm-2 s-1. Since retinoids are hydrophobic, they cannot simply diffuse from the RPE to ipRGCs but must rely on specialized transport mechanisms, which appear to be present in Müller cells.
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