Abstract
The mouse optic nerve crush (ONC) model has been widely used to study optic neuropathies and central nervous system (CNS) axon injury and repair. Previous histological studies of retinal ganglion cell (RGC) somata in retina and axons in ON demonstrate significant neurodegeneration after ONC, but longitudinal morphological and functional assessment of RGCs in living animals is lacking. It is essential to establish these assays to provide more clinically relevant information for early detection and monitoring the progression of CNS neurodegeneration. Here, we present in vivo data gathered by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and pattern electroretinogram (PERG) at different time points after ONC in mouse eyes and corresponding histological quantification of the RGC somata and axons. Not surprisingly, direct visualization of RGCs by SLO fundus imaging correlated best with histological quantification of RGC somata and axons. Unexpectedly, OCT did not detect obvious retinal thinning until late time points (14 and 28-days post ONC) and instead detected significant retinal swelling at early time points (1–5 days post-ONC), indicating a characteristic initial retinal response to ON injury. PERG also demonstrated an early RGC functional deficit in response to ONC, before significant RGC death, suggesting that it is highly sensitive to ONC. However, the limited progression of PERG deficits diminished its usefulness as a reliable indicator of RGC degeneration.
Highlights
The retinal ganglion cell (RGC) is the only neuronal type to relay visual information from retina to the brain through the optic nerve (ON), which is formed by the projection axons sent exclusively from RGCs and conveniently separated from RGCs’ cell bodies in the inner retina
Since optic neuropathy can be associated with other central nervous systems (CNS) neurodegenerative diseases (Carelli et al, 2017), ON crush (ONC) provides a CNS neurodegeneration model that can be used for studying degenerative mechanisms and evaluating neuroprotectants and regeneration therapies
To monitor the progression of neurodegeneration in vivo, the changes of ganglion cell complex (GCC) thickness were acquired at different time points after ONC: Interestingly, the initial response of the retina to ONC was an increase in GCC thickness to 110% at 1 dpc and 3 dpc followed by a return to normal thickness at 5 dpc and 7 dpc (Figures 3A,B)
Summary
The retinal ganglion cell (RGC) is the only neuronal type to relay visual information from retina to the brain through the optic nerve (ON), which is formed by the projection axons sent exclusively from RGCs and conveniently separated from RGCs’ cell bodies in the inner retina. Postmortem histological study of mouse ONC has demonstrated severe degeneration of RGC somata in retina and axons in ON, but there has been no longitudinal morphological and functional assessment of RGCs in living animals. These unmet clinical needs motivate us to develop reliable in vivo assays in a well-controlled animal model to demonstrate practical and reliable ways to longitudinally assess RGC morphology and function. This capability will provide essential clinically relevant information for early detection and monitoring of the progression of CNS neurodegeneration. PERG is very sensitive to ONC, demonstrating a significant deficit 1-day post-ONC but fails to reveal progressive impairments after the initial response
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