Behavioural NeuroscienceResearch PaperPre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1G93A ALS mouse model
Section snippets
B6.SOD1G93A transgenic mice
Experiments were performed in accordance with NIH guidelines for the use of experimental animals and approved by the University of Texas Institutional Animal Care and Use Committee. Animals were provided food and water ad libitum and housed on a 12:12 h light cycle (on at 7 am). A single male B6.Cg-Tg[SOD1-G93A]1Gur/J, hereafter referred to as B6.SOD1G93A, was purchased from The Jackson Laboratory, Bar Harbor, ME, USA (stock, 004435). These mice over-express a point mutated form of the human
Delayed tremor symptom onset in female B6.SOD1G93A mice
In B6.SOD1G93A mice, the first clinical symptoms of motor neuron disease presented as fine tremors in one or both hindlimbs when suspended by the tail (Chiu et al., 1995). Kaplan–Meier analysis revealed that tremor onset occurred significantly sooner in male (91±2 days) compared to female (100±2 days) B6.SOD1G93A mice, (P≤0.01) (Table 1). Evidence of tremor was undetected at any age in control mice. Similar to previously published results (Heiman-Patterson et al., 2005), Kaplan–Meier analysis
Discussion
The evaluation of treatment efficacy in mouse models of ALS has traditionally relied on forced exercise tasks (e.g. rotarod, paw grip endurance, treadmill, gait analysis) (Gurney et al., 1994, Kong and Xu, 1998, Weydt et al., 2003, Fischer et al., 2004, Wang et al., 2008). However, this battery of tests has proven insensitive at detecting motor deficits prior to the onset of overt clinical symptoms despite ultrastructural, histological, electrophysiological and metabolic evidence that have
Conclusion
While ∼18 different murine ALS models have contributed greatly to our current understanding of the disease mechanisms they also serve as platforms for screening candidate therapies (Turner and Talbot, 2008). An important hurdle limiting the development of neuroprotective strategies in ALS models has been the inability to detect persistent behavioral and physical changes early in the disease. This has been exacerbated by the lack of objective, non-invasive, non-technical, cost-effective and
Acknowledgments
Supported by NIH grant T32 MH065728. The authors thank Dr. Jason Shumake for his generous help. We also greatly appreciate the contributions of Sonya Sui, Samir Khatani, Anvinh Nguyen, Huma Vaid, Erin Keith, Justin Rhee, Kimi Vu, Shivam Patel, Brandon Martinez, Tameka Jones-Watlington and Gene Pershwitz.
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2020, Free Radical Biology and MedicineCitation Excerpt :To seek for in vivo pathological evidence of SOD12xS-S in ALS, we attempted to detect it in a lumbar spinal cord of an ALS-model mouse expressing G93A-mutant human SOD1 (G93A mouse). G93A mice are known to become symptomatic around 100 days of age [39], and accumulation of insoluble SOD1 in the lumbar spinal cord becomes evident after the onset of disease [40]. We hence performed our Urea-SDS-PAGE followed by Western blotting on soluble and insoluble fractions of the lumbar spinal cord homogenates of G93A mice but could not obtain clear evidence to support the presence of SOD12xS-S in both fractions (Fig. S4).