I have read with interest the article "PACAP-Deficient Mice Exhibit Light Parameter-Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset" by Chihiro Kawaguchi et al in PLoS One (2010) 5, issue 2, e9286.(1) I believe the authors' findings are of scientific interest, however I would like to provide some related findings which were proposed in 1981 with regards to the Nonvisual Retinal Ganglion cells (NVRGCs), their circuits, nonvisual pigments, associated growth factors (peptides) in the context of nonvisual photoreception.(2)

In earlier studies on human embryos at Complutense University in Madrid in 1981, I described the NVRGCs and suggested possible functions. Although the originality of these unprecedented findings and notion of the novel non-visual photoreception and their implications were too modern at that time for immediate acceptance, the “Triplex Hypothesis of Vision” was eventually published in 1993.(2) I first described the non-visual ganglion cells, their non-visual circuits, and pigments (2,4,5,9,11) which ultimately became the foundation for all future investigation in the field. The NVRGCs later, for no reason, replaced by “non-rod, non- cone” receptors and since 2002 referred to as intrinsically photosensive RGCs (IpRGCs).

I agree that PACAP is a peptide with described characteristics and is associated with NVRGCs. In my observations NVRGCs are primitive, appear mainly during embryogenesis, have interaction with the conventional ganglion cells (image forming), and act like extraretinal, extraorbital photoreceptors in the lower animal scales.(2) They carry or are associated with growth factors or peptides for their neurotrophic, neuroprotective and other functions. PACAP is one of the peptides that acts as a trophic or growth factors (2,4,5) and perform a variety of functions in the nervous system including the ones that authors have beautifully described. PACAP has a vegetative role on entrainment and masking. In addition, the ipRGCs/NVRGCs have similarities with nonvisual rhabdomeric-like sensors of lower animals like scallops(7) and amphioxus, (6,8,12) a chordate with primitive neural tube and a light sensing cells with vegetative nonvisual functions.

It has been reported that knocked out melanopsin containing ipRGCs (3) still innervate the same non-image-forming brain centers, and despite the lack of melanopsin still express some nonvisual functions. (9,10) Therefore, the NVRGCs2 with or without melanopsin are non-visual in nature while the term “ipRGCs”does not carry such meaning. These rhabdomeric-like light sensors are present in prebilaterians and most ancient living ancestors of vertebrates about 550 million years ago and suffered minimal evolutionary rearrangement of their genome. Thus NVRGCs are ancient in nature and more resistant to evolutionary changes and withstand better than conventional ganglion cells. I have alluded to the growth factors and other issues previously (2,4,5) and in various ARVO Meetings.

Lastly, I have called scientists' attention to different types of pigments and different peptides in association with the NVRGCs which mediate different functions with more meaningful terminologies.(2,4,5) Therefore, recent terms including “melanopsin” and ipRGCs” do not sufficiently explain the nonvisual physiologic characters of these cells. The terms “nonvisual pigments” and “NVRGCs” better encompass their relative functions and would assure better understanding among readers. To avoid confusion the NVRGCs, pigments and related peptides would require a classification and explanation of their origin, structures, functions and their genetic background.

In conclusion, I thank the authors for their fine study that sheds light on this complex system of receptors and peptides. I hope I clarified the stance of the old “Triplex Hypothesis of Vision” and its subsequent recent added refinements.

Ali A. Kashani, M.D.
436 North Roxbury Dr., Suite 114,
Beverly Hills, CA 90212. USA.
aakashani@yahoo.com ,
Tel: (310) 859-0290.

References

1-Kawaguchi C., Isojima Y., Shintani N., Hatanaka M., Guo X., Okumura N., Nagai K., Hashimoto H., Baba A., (2010). PACAP-Deficient mice exhibit light parameter-dependent abnormalities on nonvisual photoreception and early activity onset. PLos One 5, (2) e9286.

2-Kashani A.A. The Triplex hypothesis of vision (1993). Ann Ophthalmol. 25, 125-132.

3-Berson D.M., Dunn F.A., Takao M. (2002). Phototransduction by retinal ganglion cells that set the circadian clock. Science. 295,1070-1073.

4-Kashani A.A. (2005). Sleep disturbances. Ophthalmology. 10, 1847-1848.

5-Kashani A. A. (2009) Letter: Nonvisual ganglion cells, circuits and nonvisual pigments. Chinese Medical Jounal. 122 (18), 2199-2000.

6-Putnam N.H. (2008) The Amphioxus genome and the evolution of chordate karyotype. Nature 453, 1064-1072.

7-Kojima D., Terakita A., Ishikawa T.,Tsukahara Y., Maeda A., Shichida Y. (1997). A novel Go-mediated phototransduction cascade in scallop visual cells. J. Biol Chem 272, 22979-22982.

8-Gomez M., Angueyra J.M., Nasi E., (2009). Light-transduction in melanopsin-expressing photoreceptors of Amphioxus. PNAS. 106 ;

9-Hattar S., Kumar M., Park A., Tong P., Tung J., Yau K.W., and Berson D.M. (2006). Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J. Comp. Neurol. 497,326-349.



10-Guler A. D., Ecker J. L., Lall G. S., Hag S., Altimus C.A., 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) Letter. melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. 10-1038/Nature 06829. 1-4.

11--Gonzales-Menendez I., Contreras F., Cernuda-Cernuda R., Garcia-Fernandez J.M., (2010). No loss of melanopsin-expressing ganglion cells detected during postnatal development of the mouse retina. Histol and Histopathol. 25, 73-82.