Retinal Degeneration and Microglial Activation in Mouse Models of Neuronal Ceroid Lipofuscinoses

Abstract

Purpose: : Neuronal ceroid lipofuscinoses (NCL) are early onset lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Notably, massive accumulations of autofluorescent material in neurons lead to progressive neuronal degeneration and cell loss. Neuropathological analyses of human autopsy material and brain from NCL animal models revealed neuroimmune processes closely associated with neuronal degeneration. It is currently unclear whether this phenomenon is confined to the brain or also occurs in the retina. The aim of our study was to characterize the relationship between retinal degeneration and microglia activation in different mouse models of NCL.

Methods: : Retinal degeneration of the NCL mutant mouse strains Cln3^Δex7/8KI and Cln6^nclf was characterized by detailed structural analyses at different ages. Microglial morphology and migration was analyzed by immunohistochemistry. Visual acuity and retinal function was determined by measuring the optokinetic response in an Optomotry system and by use of electroretinography, respectively. Retinal and brain neuro-degenerative gene expression markers were compared in effort to determine if degeneration occurs in both tissues co-incidentally.

Results: : Our data show that there is a migration of microglia from the plexiform layers to the nuclear layers in CLN6^nclf and Cln3^Δex7/8KI retinas, which is consistent with an alerted state of microglia. Moreover, the shape of these cells changed from a ramified form to an amoeboid form. Histological analyses revealed that this microglial activity was accompanied by a prominent retinal degeneration. Optomotry tests showed that the CLN6^nclf and Cln3^Δex7/8KI mice had a progressive decline in visual acuity as they aged. These results were further confirmed by electroretinograms. Finally, neuro-inflammatory markers, notably microglial activation markers, are expressed earlier and at higher levels in CLN6^nclf mouse retina compared to brain.

Conclusions: : Our results identified a coincidence of microglia activation, retinal degeneration, and vision loss in CLN6^nclf and Cln3^Δex7/8KI mice. Furthermore, the early expression of neuro-inflammatory markers in the retina suggests therapies aimed at modulating these markers could be helpful in preserving vision and ameliorate neuronal brain degeneration in NCL patients.

Keywords: retinal degenerations: hereditary • microglia • inflammation