Further Characterization of the Predominant Inner Retinal Degeneration of Aging Cln3 Δex7/8 Knock-In Mice

Abstract

Neuronal ceroid lipofuscinosis (NCL) is the most common group of neurogenetic storage diseases typically beginning in childhood. The juvenile form (JNCL), also known as Batten disease, is the most common form. Vision-related problems are often an early sign, appearing prior to motor and mental deficits. We have previously investigated disease progression with age in the Cln3 KI mouse model for JNCL and showed a decline of visual acuity and a predominant decline of the inner retinal function in mice, similar to human disease. The aim of this study was to further characterize this degeneration by means of flicker ERGs. For the scotopic flicker ERG, we found a significantly lower magnitude for Cln3 KI mice already at 6 months of age for low stimulus frequencies, while the difference declines with increasing frequency. Under photopic conditions there was no magnitude difference at 6 months, but a cumulative magnitude reduction with further aging. For both conditions the phases were similar for both groups. There was a similar magnitude reduction for the responses of both the slow and fast rod pathway in the 15 Hz experiments, and there were no differences in response phase. Low-frequency flicker responses seem to be sensitive to very early disease manifestations, and while the degeneration is associated with a reduction of predominating inner retinal responses in the scotopic flash ERG, this predominance seems not to be related to a selective involvement of the slow and fast rod pathways.

Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

“…This has necessitated a detailed examination of the visual pathway, which has shown marked retinal degeneration in these patients [ 13 , 69 , 70 ]. In many forms of NCL, based on animal models, it is also often accompanied by optic nerve degeneration [ 5 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. Furthermore, mouse models have been shown to exhibit significant pathology in central visual pathways within the dorsolateral geniculate nucleus of the thalamus and visual cortex in many forms of NCL [ 42 , 60 , 61 , 62 ], and it is likely that other retinal receptive nuclei are also affected.…”