Retinal dysfunction precedes motor symptoms by several months in a CLN5 mouse model of Neuronal Ceroid Lipofuscinosis

Abstract

Purpose: The Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5) belongs to a family of neuronal ceroid lipofuscinosis (NCLs) diseases, the most common neurodegenerative disease group among children. A characteristic pathological feature in NCLs is the accumulation of autofluorescent material into lysosomes, causing progressive degeneration and atrophy in the brain. Clinically, the disease manifests as visual impairment, motor and mental deterioration, spontaneous seizures, and finally premature death. To date, there is no efficient treatment for NCLs. Here, we characterized the retinal phenotype of a CLN5 mouse model to facilitate preclinical drug screening.

Methods: A cohort of CLN5^-/- and wild-type (WT) mice was evaluated by electroretinography (ERG) between the age of 2 and 6 months in one month intervals. ERG was performed in dark- and light-adapted state in order to distinguish rod- and cone-mediated responses. In addition, we evaluated the pattern discrimination capability of mice by pattern ERG (PERG). At the end of those experiments, the eyes of mice were collected and processed for immunohistochemical analysis. Another cohort of similar mice had been previously evaluated for motor function (rotarod and grip tests) at 6.5, 7 and 7.5 months of age.

Results: The dark-adapted a-wave amplitude was diminished in CLN5^-/- mice already at 2 months of age and decreased further thereafter. A similar trend was observed in b-wave amplitude, but with a later onset at 3 months of age. A few months later (at the age of 5 months), light-adapted ERG and PERG amplitude decline started simultaneously. In another cohort of mice, rotarod performance in CLN5^-/- mice started to decrease at the age of 7 months, and grip strength at the age of 7.5 months.

Conclusions: CLN5^-/- mice develop rod-dominant progressive retinal dysfunction starting several months prior to other detectable symptoms such as motor clumsiness. Therefore, we suggest that ERG may provide the most efficient way to conduct in vivo drug screening utilizing mouse models of NCLs. In addition, early onset retinal dysfunction needs to be carefully considered when conducting behavioral testing in these mice.