Differential susceptibility of retinal ganglion cell subtypes in acute and chronic models of injury and disease

Abstract

Retinal ganglion cells (RGCs) are a heterogeneous population of neurons, comprised of numerous subtypes that work synchronously to transmit visual information to the brain. In blinding disorders such as glaucoma, RGCs are the main cell type to degenerate and lead to loss of vision. Previous studies have identified and characterized a variety of RGC subtypes in animal models, although only a handful of studies demonstrate the differential loss of these RGC subtypes in response to disease or injury. Thus, efforts of the current study utilized both chronic (bead occlusion) and acute (optic nerve crush, ONC) rat models to characterize disease response and differential loss of RGC subtypes. Bead occlusion and ONC retinas demonstrated significant RGC loss, glial reactivity and apoptosis compared to control retinas. Importantly, bead occlusion and ONC retinas resulted in differential subtype-specific loss of RGCs, with a high susceptibility for alpha- and direction selective-RGCs and preferential survival of ipRGCs. Results of this study serve as an important foundation for future experiments focused on the mechanisms resulting in the loss of RGCs in optic neuropathies, as well as the development of targeted therapeutics for RGC subtype-specific neuroprotection.

Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids

“…Within the mammalian retina, numerous subtypes of RGCs exist, with diversity based on morphology, transcriptional profile, and function ( Laboissonniere et al., 2019 ; Rheaume et al., 2018 ). In addition, numerous reports have detailed the selective susceptibility of certain RGC subtypes in disease states such as glaucoma ( Della Santina et al., 2013 ; Ou et al., 2016 ; Tran et al., 2019 ; VanderWall et al., 2020b ). Given the ability to enhance overall RGC survival within retinal organoids and assembloids, it may also be possible to study the differential susceptibility of RGC subtypes in future studies.…”

7,8-Dihydroxiflavone Maintains Retinal Functionality and Protects Various Types of RGCs in Adult Rats with Optic Nerve Transection

“…The rodent retina consists of over 46 different RGC types [ 49 ], and specific types of RGCs may have idiosyncratic responses to injury and protection [ 38 , 48 , 49 , 89 , 90 , 91 ]. For example, a particular resilience has been documented for the melanopsin expressing ipRGCs against optic nerve injury [ 27 , 38 , 63 , 92 , 93 , 94 ], excitotoxicity induced by intravitreal injection of NMDA [ 64 , 95 , 96 ], acute [ 29 ] or chronic [ 28 , 65 ] ocular hypertension, or light induced phototoxicity [ 97 ]. Our results suggest that in order of sensibility, OPN + Brn3a + (α-OFF like) are the most sensible, followed by OPN + Tbr2 + RGCs (M4 like) which are slightly more sensible than OPN + RGCs (α-like) and Brn3a + RGCs to IONT.…”

“…The α-ON sustained RGCs (M4) and the three types of ipRGCs that contain high levels of melanopsin, which we will refer to, from now on, as melanopsin expressing RGCs (m + RGCs) (M1-M3), have been shown to exhibit a particular resilience to optic nerve or retinal injuries in adult pigmented mice [ 48 , 49 ], albino [ 38 , 63 , 64 ] and pigmented rats [ 65 ], although other reports have indicated that OFF-transient α-RGCs are very susceptible to optic nerve crush in mice [ 66 ]. However, whether albino rat M4-like and α-like RGCs are resilient to optic nerve injury and responsive to DHF-afforded protection is presently unknown.…”

Retinal Protection by Sustained Nanoparticle Delivery of Oncostatin M and Ciliary Neurotrophic Factor Into Rodent Models of Retinal Degeneration

“…ONC in Long Evans rats was performed following our published protocol. 42 Complete ONC was verified by demonstrating no pupillary light reflex after lesion creation. Immediately after ONC, 4 µL of OSM-NP, CNTF-NP, or PBS alone were intravitreally injected.…”