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Recurrent axon collaterals of intrinsically photosensitive retinal ganglion cells

  • HANNAH R. JOO (a1) (a2), BETH B. PETERSON (a2), DENNIS M. DACEY (a2), SAMER HATTAR (a1) (a3) and SHIH-KUO CHEN (a1) (a4)...

Retinal ganglion cells (RGCs), the output neurons of the retina, have axons that project via the optic nerve to diverse targets in the brain. Typically, RGC axons do not branch before exiting the retina and thus do not provide it with synaptic feedback. Although a small subset of RGCs with intraretinal axon collaterals has been previously observed in human, monkey, cat, and turtle, their function remains unknown. A small, more recently identified population of RGCs expresses the photopigment melanopsin. These intrinsically photosensitive retinal ganglion cells (ipRGCs) transmit an irradiance-coding signal to visual nuclei in the brain, contributing both to image-forming vision and to several nonimage-forming functions, including circadian photoentrainment and the pupillary light reflex. In this study, using melanopsin immunolabeling in monkey and a genetic method to sparsely label the melanopsin cells in mouse, we show that a subgroup of ipRGCs have axons that branch en route to the optic disc, forming intraretinal axon collaterals that terminate in the inner plexiform layer of the retina. The previously described collateral-bearing population identified by intracellular dye injection is anatomically indistinguishable from the collateral-bearing melanopsin cells identified here, suggesting they are a subset of the melanopsin-expressing RGC type and may therefore share its functional properties. Identification of an anatomically distinct subpopulation in mouse, monkey, and human suggests this pathway may be conserved in these and other species (turtle and cat) with intraretinal axon collaterals. We speculate that ipRGC axon collaterals constitute a likely synaptic pathway for feedback of an irradiance signal to modulate retinal light responses.

Corresponding author
*Address correspondence to: Dr. Shih-Kuo Chen, Department of Zoology, National Taiwan University, Taipei, Taiwan 106. E-mail: and Dr. Samer Hattar, Departments of Biology and Neuroscience, Johns Hopkins University, Baltimore, MD 21218. E-mail:
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Badea, T., Hua, Z., Smallwood, P., Williams, J., Rotolo, T., Ye, X. & Nathans, J. (2009). New mouse lines for the analysis of neuronal morphology using CreER(T)/loxP-directed sparse labeling. PLoS One 4, e7859.
Barnard, A., Hattar, S., Hankins, M. & Lucas, R. (2006). Melanopsin regulates visual processing in the mouse retina. Current Biology: CB 16, 389395.
Baver, S.B., Pickard, G.E. & Sollars, P.J. (2008). Two types of melanopsin retinal ganglion cell differentially innervate the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus. The European Journal of Neuroscience 27, 17631770.
Belenky, M.A., Smeraski, C.A., Provencio, I., Sollars, P.J. & Pickard, G.E. (2003). Melanopsin retinal ganglion cells receive bipolar and amacrine cell synapses. The Journal of Comparative Neurology 460, 380393.
Berson, D., Castrucci, A. & Provencio, I. (2010). Morphology and mosaics of melanopsin-expressing retinal ganglion cell types in mice. The Journal of Comparative Neurology 518, 24052422.
Berson, D.M., Dunn, F.A. & Takao, M. (2002). Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 10701073.
Brown, T.M., Gias, C., Hatori, M., Keding, S.R., Semo, M., Coffey, P.J., Gigg, J., Piggins, H.D., Panda, S. & Lucas, R.J. (2010). Melanopsin contributions to irradiance coding in the thalamo-cortical visual system. PLoS Biol 8, e1000558.
Chen, S.K., Badea, T.C. & Hattar, S. (2011). Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature 476, 9295.
Dacey, D.M. (1985). Wide-spreading terminal axons in the inner plexiform layer of the cat’s retina: Evidence for intrinsic axon collaterals of ganglion cells. The Journal of Comparative Neurology 242, 247262.
Dacey, D.M., Liao, H-W., Peterson, B.B., Robinson, F.R., Smith, V.C., Pokorny, J., Yau, K-W. & Gamlin, P.D. (2005). Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 433, 749754.
Dacey, D.M., Peterson, B.B., Liao, H-W. & Yau, K-W. (2006). Two types of melanopsin-containing ganglion cell in the primate retina: Links to dopaminergic amacrine and DB6 cone bipolar cells. Investigative Ophthalmology & Visual Science 47, ARVO E-Abstract 3111.
Dowling, J.E. & Ehinger, B. (1975). Synaptic organization of the amine-containing interplexiform cells of the goldfish and Cebus monkey retina. Science 188, 270273.
Ecker, J.L., Dumitrescu, O.N., Wong, K.Y., Alam, N.M., Chen, S.K., Legates, T., Renna, J.M., Prusky, G.T., Berson, D.M. & Hattar, S. (2010). Melanopsin-expressing retinal ganglion-cell photoreceptors: Cellular diversity and role in pattern vision. Neuron 67, 4960.
Famiglietti, E.V. Jr. (1983). ‘Starburst’ amacrine cells and cholinergic neurons: Mirror-symmetric on and off amacrine cells of rabbit retina. Brain Research 261, 138144.
Gallego, A. & Cruz, J. (1965). Mammalian retina: Associational nerve cells in ganglion cell layer. Science 150, 13131314.
Gamlin, P.D., McDougal, D.H., Pokorny, J., Smith, V.C., Yau, K-W. & Dacey, D.M. (2007). Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells. Vision Research 47, 946954.
Goz, D., Studholme, K., Lappi, D.A., Rollag, M.D., Provencio, I. & Morin, L.P. (2008). Targeted destruction of photosensitive retinal ganglion cells with a saporin conjugate alters the effects of light on mouse circadian rhythms. PLoS One 3, e3153.
Guler, A.D., Ecker, J.L., Lall, G.S., Haq, S., Altimus, C.M., Liao, H.W., Barnard, A.R., Cahill, H., Badea, T.C., Zhao, H., Hankins, M.W., Berson, D.M., Lucas, R.J., Yau, K.W. & Hattar, S. (2008). Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature 453, 102105.
Hatori, M., Le, H., Vollmers, C., Keding, S.R., Tanaka, N., Schmedt, C., Jegla, T. & Panda, S. (2008). Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses. PLoS One 3, e2451.
Hattar, S., Kumar, M., Park, A., Tong, P., Tung, J., Yau, K. & Berson, D. (2006). Central projections of melanopsin-expressing retinal ganglion cells in the mouse. The Journal of Comparative Neurology 497, 326349.
Hattar, S., Liao, H.W., Takao, M., Berson, D.M. & Yau, K.W. (2002). Melanopsin-containing retinal ganglion cells: Architecture, projections, and intrinsic photosensitivity. Science 295, 10651070.
Hayashida, Y. & Ishida, A.T. (2004). Dopamine receptor activation can reduce voltage-gated Na+ current by modulating both entry into and recovery from inactivation. Journal of Neurophysiology 92, 31343141.
Honrubia, F.M. & Elliott, J.H. (1968). Efferent innervation of the retina I. Morphologic study of the human retina. Archives of Ophthalmology 80, 98103.
Ichinose, T. & Lukasiewicz, P.D. (2007). Ambient light regulates sodium channel activity to dynamically control retinal signaling. Journal of Neuroscience 27 17, 47564764.
Indra, A.K., Warot, X., Brocard, J., Bornert, J.M., Xiao, J.H., Chambon, P. & Metzger, D. (1999). Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: Comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Research 27, 43244327.
Jusuf, P.R., Lee, S.C., Hannibal, J. & Grunert, U. (2007). Characterization and synaptic connectivity of melanopsin-containing ganglion cells in the primate retina. The European Journal of Neuroscience 26, 29062921.
Lasater, E.M. & Dowling, J.E. (1985). Dopamine decreases conductance of the electrical junctions between cultured retinal horizontal cells. Proceedings of the National Academy of Sciences of the United States of America 82, 30253029.
LeGates, T.A., Altimus, C.M., Wang, H., Lee, H.K., Yang, S., Zhao, H., Kirkwood, A., Weber, E.T. & Hattar, S. (2012). Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature 491, 594598.
Lobe, C.G., Koop, K.E., Kreppner, W., Lomeli, H., Gertsenstein, M. & Nagy, A. (1999). Z/AP, a double reporter for cre-mediated recombination. Developmental Biology 208, 281292.
Lucas, R.J., Hattar, S., Takao, M., Berson, D.M., Foster, R.G. & Yau, K.W. (2003). Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245247.
Mariani, A.P. & Hersh, L.B. (1988). Synaptic organization of cholinergic amacrine cells in the rhesus monkey retina. The Journal of Comparative Neurology 267, 269280.
Nir, I., Harrison, J., Haque, R., Low, M., Grandy, D., Rubinstein, M. & Iuvone, P. (2002). Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. Journal of Neuroscience 22, 20632073.
Panda, S., Provencio, I., Tu, D.C., Pires, S.S., Rollag, M.D., Castrucci, A.M., Pletcher, M.T., Sato, T.K., Wiltshire, T., Andahazy, M., Kay, S.A., Van Gelder, R.N. & Hogenesch, J.B. (2003). Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525527.
Panda, S., Sato, T.K., Castrucci, A.M., Rollag, M.D., DeGrip, W.J., Hogenesch, J.B., Provencio, I. & Kay, S.A. (2002). Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 22132216.
Percival, K.A., Martin, P.R. & Grunert, U. (2011). Synaptic inputs to two types of koniocellular pathway ganglion cells in marmoset retina. The Journal of Comparative Neurology 519, 21352153.
Peterson, B.B. & Dacey, D.M. (1998). Morphology of human retinal ganglion cells with intraretinal axon collaterals. Visual Neuroscience 15, 377387.
Provencio, I., Rollag, M.D. & Castrucci, A.M. (2002). Photoreceptive net in the mammalian retina. Nature 415, 493494.
Raven, M.A., Eglen, S.J., Ohab, J.J. & Reese, B.E. (2003). Determinants of the exclusion zone in dopaminergic amacrine cell mosaics. The Journal of Comparative Neurology 461, 123136.
Renna, J.M., Weng, S. & Berson, D.M. (2011). Light acts through melanopsin to alter retinal waves and segregation of retinogeniculate afferents. Nature Neuroscience 14, 827829.
Rodieck, R.W. (1989). Starburst amacrine cells of the primate retina. The Journal of Comparative Neurology 285, 1837.
Sakai, H.M., Naka, K-I. & Dowling, J.E. (1986). Ganglion cell dendrites are presynaptic in catfish retina. Nature 319, 495497.
Schmidt, T.M. & Kofuji, P. (2009). Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. Journal of Neuroscience 29, 476482.
Sekaran, S., Foster, R.G., Lucas, R.J. & Hankins, M.W. (2003). Calcium imaging reveals a network of intrinsically light-sensitive inner-retinal neurons. Current Biology: CB 13, 12901298.
Usai, C., Ratto, G.M. & Bisti, S. (1991). Two systems of branching axons in monkey’s retina. The Journal of Comparative Neurology 308, 149161.
Viney, T.J., Balint, K., Hillier, D., Siegert, S., Boldogkoi, Z., Enquist, L.W., Meister, M., Cepko, C.L. & Roska, B. (2007). Local retinal circuits of melanopsin-containing ganglion cells identified by transsynaptic viral tracing. Current Biology: CB 17, 981988.
Vugler, A., Redgrave, P., Semo, M., Lawrence, J., Greenwood, J. & Coffey, P. (2007). Dopamine neurones form a discrete plexus with melanopsin cells in normal and degenerating retina. Experimental Neurology 205, 2635.
Wässle, H. & Boycott, B.B. (1991). Functional architecture of the mammalian retina. Physiological Reviews 71, 447480.
Zhang, D.Q., Belenky, M.A., Sollars, P.J., Pickard, G.E. & McMahon, D.G. (2012). Melanopsin mediates retrograde visual signaling in the retina. PLoS One 7, e42647.
Zhang, D.Q., Wong, K.Y., Sollars, P.J., Berson, D.M., Pickard, G.E. & McMahon, D.G. (2008). Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons. Proceedings of the National Academy of Sciences of the United States of America 105, 1418114186.
Zhang, D.Q., Zhou, T.R. & McMahon, D.G. (2007). Functional heterogeneity of retinal dopaminergic neurons underlying their multiple roles in vision. Journal of Neuroscience 27, 692699.
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Visual Neuroscience
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