Neurodevelopmental delay in the Cln3^Δex7/8 mouse model for Batten disease

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease, is a fatal inherited neurodegenerative disorder. The major clinical features of this disease are vision loss, seizures and progressive cognitive and motor decline starting in childhood. Mutations in CLN3 are known to cause the disease, allowing the generation of mouse models that are powerful tools for JNCL research. In this study, we applied behavioural phenotyping protocols to test for early behavioural alterations in Cln3Dex7/8 knock-in mice, a genetic model that harbours the most common disease-causing CLN3 mutation. We found delayed acquisition of developmental milestones, including negative geotaxis, grasping, wire suspension time and postural reflex in both homozygous and heterozygous Cln3Dex7/8 preweaning pups. To further investigate the consequences of this neurodevelopmental delay, we studied the behaviour of juvenile mice and found that homozygous and heterozygous Cln3Dex7/8 knock-in mice also exhibit deficits in exploratory activity. Moreover, when analysing motor behaviour, we observed severe motor deficits in Cln3Dex7/8 homozygous mice, but only a mild impairment in motor co-ordination and ambulatory gait in Cln3Dex7/8 heterozygous animals. This study reveals previously overlooked behaviour deficits in neonate and young adult Cln3Dex7/8 mice indicating neurodevelopmental delay as a putative novel component of JNCL.

Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

“…S1). It is noteworthy that our results are not in agreement with the findings reported by Osorio et al [27] in which 8-week-old homozygous Cln3 Δ ex7/8 mice on a C57BL/6J background were found to have reduced exploratory activity (reduced rearing frequency and vertical locomotion) and to spend less time in the center of the chamber in an open field assay.…”

“…Again in contrast to the Osorio et al study [27], in which 8-week homozygous Cln3 Δ ex7/8 mice on a C57BL/6J background were reported to perform more poorly than wild-type mice on an accelerating rotarod, we found no genotypic differences in accelerating rotarod performance in 10- to 11-week-old Cln3 Δ ex7/8 mice on the C57BL/6N background (Fig. S3).…”

“…However, inconsistencies between our results here and the results of behavioral studies performed on Cln3 Δ ex7/8 mice by other groups [27], [49] also clearly indicate the need for standardized mouse behavioral testing paradigms. The differences in the performance of Cln3 Δ ex7/8 mice in rotarod and open field assays across this study and the studies described in other reports may be attributable to equipment differences, methodology, data analysis, testing age, genetic background, and/or environmental influences.…”

Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3Δex7/8-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis

“…Osorio et al (2009) recently reported an impaired motor performance of 8-week-old Cln3 Δex7/8 mice in a constant speed rotarod test. Using a more challenging, accelerating rotarod test (0-37 rpm in 120 s), we found that Cln3 Δex7/8 mice already have a motor coordination deficit at the age of 7 weeks (Fig.…”

“…This motor deficit, that can be detected as early as on postnatal day 14, has been characterized using an accelerating rotarod test (0–30 rpm in 240 s) (Kovacs and Pearce, 2008; Kovacs et al, 2006; Weimer et al, 2009). Osorio et al (2009) recently reported an impaired motor performance of 8-week-old Cln3 Δex7/8 -knock-in mice in a constant speed rotarod test. Applying a more challenging, accelerating rotarod test (0-37 rpm in 120 s), we were able to detect the motor coordination deficit in 7-week-old Cln3 Δex7/8 -knock-in mice (see Fig.…”