Optogenetic Stimulation of the Superior Colliculus Confers Retinal Neuroprotection in a Mouse Glaucoma Model

Abstract

Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) in the eye, which ultimately results in visual impairment or even blindness. Because current therapies often fail to halt disease progression, there is an unmet need for novel neuroprotective therapies to support RGC survival. Various research lines suggest that visual target centers in the brain support RGC functioning and survival. Here, we explored whether increasing neuronal activity in one of these projection areas could improve survival of RGCs in a mouse glaucoma model. Prolonged activation of an important murine RGC target area, the superior colliculus (SC), was established via a novel optogenetic stimulation paradigm. By leveraging the unique channel kinetics of the stabilized step function opsin (SSFO), protracted stimulation of the SC was achieved with only a brief light pulse. SSFO-mediated collicular stimulation was confirmed by immunohistochemistry for the immediate-early gene c-Fos and behavioral tracking, which both demonstrated consistent neuronal activity upon repeated stimulation. Finally, the neuroprotective potential of optogenetic collicular stimulation was investigated in mice of either sex subjected to a glaucoma model and a 63% reduction in RGC loss was found. This work describes a new paradigm for optogenetic collicular stimulation and a first demonstration that increasing target neuron activity can increase survival of the projecting neurons.Despite glaucoma being a leading cause of blindness and visual impairment worldwide, no curative therapies exist. This study describes a novel paradigm to reduce retinal ganglion cell (RGC) degeneration underlying glaucoma. Building on previous observations that RGC survival is supported by the target neurons to which they project and using an innovative optogenetic approach, we increased neuronal activity in the mouse superior colliculus, a main projection target of rodent RGCs. This proved to be efficient in reducing RGC loss in a glaucoma model. Our findings establish a new optogenetic paradigm for target stimulation and encourage further exploration of the molecular signaling pathways mediating retrograde neuroprotective communication.

Advances in Ophthalmic Optogenetics: Approaches and Applications

“…The recent advances in optogenetics have also been applied to the field of glaucoma [ 5 , 6 , 63 ]. Glaucoma comprises a group of progressive optic neuropathies characterized by an abnormal increase in intraocular pressure (IOP), which damages the optic nerve over time and consequently results in injury and eventual loss of RGCs and retinal nerve fiber layers [ 64 ].…”

New perspectives of immunomodulation and neuroprotection in glaucoma

“…Apart from NTF administration, other projects have focused on stimulating NTF production. Stimulation of the superior colliculus utilizing an optogenetic approach led to an increase in BDNF production and reduced RGC loss in a murine glaucoma model [ 45 , 47 ].…”

Target-Derived Neurotrophic Factor Deprivation Puts Retinal Ganglion Cells on Death Row: Cold Hard Evidence and Caveats

“…Instead of a continuous and possible overkilled supplementation of a single NTF, we opted to focus on controlled stimulation of neuronal activity. As such, we explored whether controlled stimulation of neuronal activity in the main retinofugal murine target area, i.e., the SC, conferred neuroprotection in a glaucoma model [172]. To attain such a protracted stimulation, we used optogenetics due to its superior spatial resolution in comparison with other stimulation modalities.…”

“…Following RGC quantification, the optogenetically stimulated group showed a significant increase in surviving RGCs (90%) as compared to the unstimulated group (74%). Thereby, we showed that repeated stimulation of neuronal activity in the SC is neuroprotective for RGCs subjected to glaucomatous injury, plausibly by an increase in the production and transport of a vital target-derived NTF cocktail (Figure 3) [172]. Notably, although we focused on neuronal activation, we believe that optogenetic stimulation might affect the complete astroglial-neural network.…”

“…Ultimately, appropriate therapeutic manipulation of survival factors and/or downstream signaling pathways important for target-derived RGC survival might result in the design of an efficient, long-term neuroprotective treatment. In our study, we exclusively stimulated neuronal activity in the target area whilst excluding RGC activation to bring in a verdict around the importance of target areas in RGC neuroprotection [172]. However, as it has been shown that local stimulation also entails neuroprotective effects—see Section 5.3—, both target and local stimulation might be employed in synergy to lever RGC survival.…”