Novel behavioural characteristics of the superoxide dismutase 1 G93A (SOD1^G93A) mouse model of amyotrophic lateral sclerosis include sex‐dependent phenotypes

Abstract

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.

Medium-Dose Chronic Cannabidiol Treatment Reverses Object Recognition Memory Deficits of APPSwe/PS1ΔE9 Transgenic Female Mice

“…The current study found that the overall ability to acquire the CB and reversal CB task (i.e., the ability to learn the position of a food reward within the overall training period) was not affected in 12-month-old APPxPS1 mice and that CBD did not affect spatial learning when considering intermediateterm and reference memory. Investigating CB learning in that detail has only recently been described (Kreilaus et al, 2019); thus, this is the first study to identify that the intermediate-term and long-term retention learning memory of 12-month-old APPxPS1 female mice appear intact. Interestingly, spatial learning and reversal spatial learning of the APPxPS1 mice were delayed by one day when considering performance across three daily trials compared to WT mice on a day-to-day basis.…”

“…An accelerating rotarod paradigm was used to measure the motor coordination and balance of the test mice ( Brooks and Dunnett, 2009 ). Training and testing were carried out as described previously ( Kreilaus et al, 2019 ), but with two consecutive test days with two trials per day. The mean of the four trials was considered for analysis, as was the worst-performing trial.…”

“…The innate preference of a mouse for novelty and its ability to distinguish a novel object from a familiar object ( Dere et al, 2007 ) are utilized in this test to determine object recognition memory. The NORT was conducted as published previously ( Kreilaus et al, 2019 ). The percentage of time spent nosing the novel object during the second “testing” trial was calculated as and it was used as an indication of object recognition memory.…”

“…Spatial memory was assessed through the cheeseboard (CB) paradigm. Details on the apparatus used can be found in previous studies from our lab ( Cheng et al, 2013 ; Kreilaus et al, 2019 ; Watt et al, 2020 ). Briefly, mice were habituated over two days to the blank side of the board (i.e., 3 × 2 min trials per day, 20 min ITI).…”

Sex differences in 3D: Differentiation, dimorphism, or dependence?

“…USVs also play a key role in pup‐mother communication, and Nolan et al find that male and female Fmr1 (a gene linked to fragile X syndrome) knockout or heterozygous mice exhibit discrete patterns of altered vocalizations compared with their wildtype, same‐sex littermates. Finally, in a mutant mouse model of amyotrophic lateral sclerosis (ALS), Kreilaus et al report that prior to the onset of expected motor deficits, mutant males, but not females exhibited reduced sociability, pointing to a potential sex‐specific early marker of the disease.…”