Melatonin modulates M4-type ganglion-cell photoreceptors
Introduction
Melatonin is a hormone synthesized and secreted by the pineal gland and other tissues including the retina (Lerner et al., 1958, Cardinali and Rosner, 1971, Bubenik et al., 1974, Tosini and Menaker, 1996, Stefulj et al., 2001). Although the biochemistry and physiological actions of melatonin have been investigated extensively, its roles in the retina remain poorly understood. Melatonin is secreted at night by rod/cone photoreceptors and the melatonin receptors MT1 and MT2 have been detected in all five classes of retinal neurons including rod/cone photoreceptors, horizontal cells, bipolar cells, amacrine cells and ganglion cells, suggesting this hormone performs diverse neuromodulatory functions (Huang et al., 2013, Wiechmann and Sherry, 2013).
Two recent studies reported the expression of melatonin receptors in intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice and rats (Sengupta et al., 2011, Sheng et al., 2015). IpRGCs are inner retinal photoreceptors that contain the photopigment melanopsin and mediate not only pattern vision but also non-image-forming visual responses such as pupillary constriction and circadian photoentrainment (Do and Yau, 2010, Ecker et al., 2010, Schmidt et al., 2014). Though ipRGCs are directly light-sensitive, they nevertheless receive rod/cone-driven synaptic input through bipolar and amacrine cells (Wong et al., 2007, Zhao et al., 2014). Thus, melatonin could modulate ipRGCs by acting either directly on them or on their presynaptic circuits, or both. Here, we tested this hypothesis by focusing on the alpha-like M4-type ipRGCs, whose unusually large somas enable them to be identified for whole-cell recordings with relative ease (Estevez et al., 2012, Schmidt et al., 2014, Reifler et al., 2015), thereby obviating the need for fluorescent labeling (Berson et al., 2002, Ecker et al., 2010). We studied the effects of exogenous and endogenous melatonin on M4 cells’ resting membrane potential, spontaneous spike rate, rod/cone-driven (“extrinsic”) light responses, and melanopsin-mediated (“intrinsic”) light responses. We also looked for the expression of melatonin receptors in these neurons.
Section snippets
Ethical approval
All experimental procedures were approved by the University Committee on Use and Care of Animals at the University of Michigan, and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23). All efforts were made to minimize the number of animals used and their suffering.
Animals
A total of ∼150 male and female Sprague–Dawley rats aged 2–4 months were used. The animals were maintained in a 12-h light, 12-h dark
Daytime melatonin application modulates M4 cells’ extrinsic light responses
We examined the effects of exogenous melatonin during the animals’ subjective day, when endogenous melatonin secretion is low (Cahill and Besharse, 1992, Tosini and Menaker, 1996). In normal Ames’ medium, M4 cells had a resting membrane potential of −63.1 ± 1.2 mV and spiked spontaneously at 36.7 ± 6.2 Hz. Bath application of 10 nM melatonin had no significant effects on either of these resting properties (Fig. 1B, C). By contrast, extrinsic photoresponses were significantly altered. In response to a 1
Discussion
To date, only two studies have investigated neuromodulation of ipRGC physiology: dopaminergic modulation of M1 cells (Van Hook et al., 2012), and adenosinergic modulation of unclassified ipRGCs (Sodhi and Hartwick, 2014). The present work focused on the M4 type because it is relatively easy to identify for whole-cell recordings. Considering that M4 cells contribute to image-forming as well as non-image-forming vision (Estevez et al., 2012, Schmidt et al., 2014), our results suggest that
Author contributions
D.D.H. conducted pilot experiments and made the recordings shown in Fig. 5A; W.P. generated and analyzed all other electrophysiological data; K.Y.W. conceived the project, designed the research, performed the immunohistochemistry and confocal imaging, and wrote the manuscript. All authors reviewed and approved the final version of the manuscript.
Acknowledgments
This work was funded by National Eye Institute (NEI) Grant R00 EY018863 to K.Y.W., a Research to Prevent Blindness Scientific Career Development Award to K.Y.W., National Science Foundation Graduate Student Research Fellowship DGE 1256260 to D.D.H., and NEI Grant P30 EY007003 to the Kellogg Eye Center.
References (66)
- et al.
Immunohistological localization of N-acetylindolealkylamines in pineal gland, retina and cerebellum
Brain Res
(1974) - et al.
Electrophysiological effects of tachykinin analogues on ganglion cell activity in cyprinid fish retina
Neuropeptides
(1993) - et al.
Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision
Neuron
(2010) - et al.
Expression of mt1 melatonin receptor in rat retina: evidence for multiple cell targets for melatonin
Neuroscience
(1999) - et al.
Inner plexiform circuits in the carp retina: effects of cholinergic agonists, GABA, and substance P on the ganglion cells
Brain Res
(1982) - et al.
5-HT2A receptors are differentially expressed in bullfrog and rat retinas: a comparative study
Brain Res Bull
(2007) - et al.
Activation of melatonin receptor increases a delayed rectifier K+ current in rat cerebellar granule cells
Brain Res
(2001) - et al.
Neuromodulatory role of melatonin in retinal information processing
Prog Retin Eye Res
(2013) - et al.
The rat retina has five types of ganglion-cell photoreceptors
Exp Eye Res
(2015) - et al.
AII amacrine cells express the MT1 melatonin receptor in human and macaque retina
Exp Eye Res
(2003)
A role for melanopsin in alpha retinal ganglion cells and contrast detection
Neuron
Role of melatonin and its receptors in the vertebrate retina
Int Rev Cell Mol Biol
Circadian rhythm in rat retinal dopamine
Neurosci Lett
Photoreceptor adaptation in intrinsically photosensitive retinal ganglion cells
Neuron
Melatonin inhibits tetraethylammonium-sensitive potassium channels of rod ON type bipolar cells via MT2 receptors in rat retina
Neuroscience
Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor
Proc Nat Acad Sci U S A
Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function
Sci Signal
Dark adaptation is faster in pigmented than albino rats
Adv Ophthalmol
Phototransduction by retinal ganglion cells that set the circadian clock
Science
Phosphorylation of mouse melanopsin by protein kinase A
PLoS One
The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin
Braz J Med Biol Res
Light-sensitive melatonin synthesis by Xenopus photoreceptors after destruction of the inner retina
Vis Neurosci
Retinal localization of the hydroxyindole-O-methyl transferase (HIOMT) in the rat
Endocrinology
Intrinsically photosensitive retinal ganglion cells
Physiol Rev
Circadian rhythmicity in dopamine content of mammalian retina: role of the photoreceptors
J Neurochem
Melatonin is a potent modulator of dopamine release in the retina
Nature
Form and function of the M4 cell, an intrinsically photosensitive retinal ganglion cell type contributing to geniculocortical vision
J Neurosci
Dopaminergic and GABAergic amacrine cells are direct targets of melatonin: immunocytochemical study of mt1 melatonin receptor in guinea pig retina
Vis Neurosci
Targeted destruction of photosensitive retinal ganglion cells with a saporin conjugate alters the effects of light on mouse circadian rhythms
PLoS One
Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision
Nature
Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses
PLoS One
International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)
Pharmacol Rev
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