Behavioural effects of cage systems on the G93A Superoxide Dismutase 1 transgenic mouse model for amyotrophic lateral sclerosis.

Environmental factors inherent to animal facilities can impact on the neuro-behavioural phenotype of laboratory mice and genetic mouse models for human diseases. Many facilities have upgraded from traditional 'open filter top' cages (FT) to individually ventilated cage (IVC) systems, which have been shown to modify various behavioural responses of laboratory mice. Importantly, the impact of IVC housing on the G93A superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis (ALS) is currently unknown. Male and female wild type-like (WT) and heterozygous SOD1G93A mice were group-housed in FT or IVC systems from PND 30 ± 5 onwards. Body weight and motor function were assessed weekly from 15 weeks onward. Mice were also tested for cognitive abilities (i.e., fear conditioning and social recognition memory) and sensorimotor gating (i.e., prepulse inhibition: PPI). SOD1G93A mice lost body weight, and their motor function degenerated over time compared with control littermates. Motor impairments developed faster when SOD1G93A females were housed in IVCs. Context and cue freezing were increased in SOD1G93A females compared with controls, whereas all SOD1G93A mice exhibited lower acoustic startle and PPI than WT mice. IVC housing led to an increase in cue freezing in males and reduced the severity of PPI deficits in SOD1G93A females. Overall, IVC housing impacted moderately on the SOD1G93A phenotype but central behavioural deficits were still evident across housing conditions. Nonetheless, our findings indicate the importance of assessing the effect of cage system in genetic mouse models as these systems can modulate the magnitude and onset of genotypic differences.

Effects of handling on the behavioural phenotype of the neuregulin 1 type III transgenic mouse model for schizophrenia.

Handling of laboratory mice affects animal wellbeing and behavioural test outcomes. However, present research has focused on handling effects in common strains of laboratory mice despite the knowledge that environmental factors can modify established phenotypes of genetic mouse models. Thus, we examined the impact of handling on the face validity of a transgenic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. Nrg1 type III overexpression). Nrg1 III tg and wild type-like (WT) control mice of both sexes underwent tail or tunnel handling before being assessed in the open field (OF), elevated plus maze (EPM), social preference/novelty, prepulse inhibition, and fear conditioning tests. Tunnel-handling reduced the startle response in all mice, increased OF locomotion and exploration in males and reduced anxiety in males (OF) and females (EPM) compared to tail-handling. Importantly, tunnel handling induced a more pronounced startle response to increasing startle stimuli in Nrg1 III tg females compared to respective controls, a phenomenon absent in tail-handled females. Finally, Nrg1 III tg males displayed reduced OF exploration and centre locomotion and Nrg1 III tg females displayed increased cue freezing over time compared to controls. In conclusion, handling methods have a significant impact on a variety of behavioural domains thus the impact of routine handling procedures need be considered when testing behavioural phenotypes. Handling did not change the main schizophrenia-relevant characteristics of Nrg1 III tg mice but affected the acoustic startle-response in a genotype- and sex-specific manner. Future research should evaluate the effect of handling on other genetic models.

Novel behavioural characteristics of the superoxide dismutase 1 G93A (SOD1G93A ) mouse model of amyotrophic lateral sclerosis include sex-dependent phenotypes.

Amyotrophic lateral sclerosis (ALS) involves the rapid degeneration of upper and lower motor neurons leading to weakening and paralysis of voluntary movements. Mutations in copper-zinc superoxide dismutase 1 (SOD1) are a known genetic cause of ALS, and the SOD1 G93A mouse has been used extensively to investigate molecular mechanisms in ALS. In recent years, evidence suggests that ALS and frontotemporal dementia form a spectrum disorder ranging from motor to cognitive dysfunctions. Thus, we tested male and female SOD1 G93A mice for the first time before the onset of debilitating motor impairments in behavioural domains relevant to both ALS and frontotemporal dementia. SOD1 G93A males displayed reduced locomotion, exploration and increased anxiety-like behaviours compared with control males. Intermediate-term spatial memory was impaired in SOD1 G93A females, whereas long-term spatial memory deficits as well as lower acoustic startle response, and prepulse inhibition were identified in SOD1 G93A mice of both sexes compared with respective controls. Interestingly, SOD1 G93A males exhibited an increased conditioned cue freezing response. Nosing behaviours were also elevated in both male and female SOD1 G93A when assessed in social paradigms. In conclusion, SOD1 G93A mice exhibit a variety of sex-specific behavioural deficits beyond motor impairments supporting the notion of an ALS-frontotemporal spectrum disorder. Thus, SOD1 G93A mice may represent a useful model to test the efficacy of therapeutic interventions on clinical symptoms in addition to declining motor abilities.