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Lieve K M Moons, Marie Claes, Eline Dekeyster, Lut Arckens, Manuel Salinas-Navarro, Emiel Geeraerts; Optogenetic brain stimulation as a neuroprotective strategy in murine experimental glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2577.
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© ARVO (1962-2015); The Authors (2016-present)
The central brain targets of retinal ganglion cells (RGCs) are well known being essential for the survival and activity of their retinal projection neurons. To test whether the bidirectional circuit between the brain and the RGCs could be exploited as a neuroprotective strategy in glaucoma, we performed a series of experiments in which the major RGC projection area in the mouse, the superior colliculus (SC), was optogenetically activated in an established experimental mouse glaucoma model.
To enable optogenetic activation of the SC, male and female C57/Bl6 mice were injected in the right SC with an adeno-associated viral vector coding for the stable step-function opsin (SSFO). This channelrhodopsin-2 mutant has slow closing kinetics, with a time constant of 30 minutes, thus facilitating prolonged neuronal activation. Four weeks later, an optic fiber was implanted above the SC to allow light-mediated activation of the SSFO. Following a recovery period of one week, animals were subjected to the previously described laser-induced ocular hypertension model (OHT), in which the perilimbal and episcleral vessels were photocauterized, resulting in an ocular pressure increase and glaucoma-like RGC loss. Starting one day before OHT induction, the experimental group received light stimulation twice daily, with a light pulse of 2s and 2,2 mW, until the animals were sacrificed two weeks later. Control animals underwent all procedures but no light stimulation. Neuroprotection was assessed by automated quantification of RGCs on Brn3a-stained retinal flatmounts.
The optogenetically-stimulated animals showed an average RGC survival of 91 ± 3% (N=18) versus only 75 ± 5% (N=17) in the control group at 14 days post ONC, as compared to naive untreated eyes. One-way ANOVA followed by Bonferroni post-hoc tests indicated significant differences in ONC-induced RGC loss between the light-stimulated and non-stimulated mice.
Optogenetically-induced neuronal activation of the SC results in a 16% increase in RGC survival in an experimental mouse glaucoma model, and thus clearly provides neuroprotection of the retinal projection neurons. These findings show that central brain targets can play a prominent role in protecting RGCs, thus unveiling exciting new possible treatment paradigms for glaucoma and other optic neuropathies.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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