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Melina Isabel Morkin, Ephraim Trakhtenberg, Wolfgang Pita-Thomas, Stephanie Fernandez, Praseeda Venugopalan, Yan Wang, Vittorio Porciatti, Jeffrey L Goldberg; Serotonin modulates retinal ganglion cell axon growth and excitability through developmentally regulated serotonin receptor 2C.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2446.
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© ARVO (1962-2015); The Authors (2016-present)
In our search for intrinsic mediators of axon growth, we found that a number of serotonin receptors are developmentally regulated in retinal ganglion cells (RGCs), and more interestingly, in response to Kruppel-like transcription factors. It is known that serotonin is secreted in the retina, but its role in retinal physiology remains unknown. The purpose of this study is to investigate the role of serotonin receptors in the development, physiology and neurite outgrowth of retinal ganglion cells.
E20 and P8 RGCs were transfected with adenine-to-guanine edited (A->G) or unedited 5HTR2C or GFP control, incubated with 5HT or mianserin (inverse agonist, I.A.), to assess neurite length. P5 RGCs from 5HTR2C KO mice and wild-type littermates were incubated with 5HT or growth media alone, and analyzed for neurite length. P8 RGCs were transfected with 5HTR7 or mCherry, and incubated with 5HT, methiothepin (IA) or growth media alone, to quantify neurite growth. P8 RGCs were also transfected with 5HTR5A or mCherry, and incubated with or without 5HT. Adult mouse retinal cross-sections were studied to show 5HT+/ChAT-, 5HT-/ChAT+, 5HT+/TH+ and 5HT-/TH+ amacrine cells. Intracellular calcium recordings were performed on purified P5 rat RGCs cultured for 2 days, loaded with calcium dye, and stimulated with KCl positive control or with 5HTR2C agonist (WAY-161503). pERGs were also done on 5HTR2C KO and wilt-type adult mice.
Serotonin promotes neurite growth of embryonic but not postnatal RGCs. 5HTR2C, 5HTR5A, and 5HTR7 suppress RGC neurite growth. The adult mouse retina contains ~120 randomly distributed 5ht+/ChAT- amacrine cells, of which 90% are TH+. 5HTR2C regulates RGC calcium dynamics in vitro and electrical activity in vivo.
Serotonin modulation of electrical activity and neurite growth regulate retinal ganglion cell physiology, axon growth and regeneration. Modulating 5HT-2C signaling may provide an avenue to promote axon regeneration after injury or in neurodegenerative diseases.
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