Accurate quantification of tetanus neurotoxin-induced focal spasticity in mice using complex running wheels.
Tetanus neurotoxin (TeNT) enhances activity of motoneurons by blocking spinal inhibitory interneurons. Based on this pathomechanism, we propose that low-dosage intramuscular injections of TeNT could serve as a specific treatment for central paretic muscles. However in vivo TeNT research is restricted because of the fear of triggering widespread muscle spasms. In addition, no reliable test to measure the in vivo toxicity of low-dosage TeNT is available. We introduce a novel wheel running-based paradigm with mice to quantify functional effects and thus the toxicity of low-dosage TeNT in vivo. We accustomed three groups of wildtype mice (n=14) to using a complex running wheel with irregularly spaced crossbars. Each group received an injection with a different low-dosage of TeNT (0.15 ng, 0.1 ng or 0.05 ng TeNT) into both tibialis anterior muscles. The maximum running velocity and accumulative running time of the groups were recorded during the following weeks. Three days after TeNT injections, the mice exhibited an increase in muscle tone of the injected tibialis anterior muscles but no generalized symptoms. However, we found that normal running in the complex wheel set-up was disturbed such that the maximum running velocity and running time of the mice decreased with the size of the dose. This effect peaked on the fifth and sixth nights after injection and returned to baseline level again within the next two weeks. With this novel in vivo automated paradigm we can accurately and objectively quantify the duration and degree of TeNT-induced focal increase in muscle tone.
Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert-Koch-Strasse 40, 37099 Göttingen, Germany. anna.kutschenko@med.uni-goettingen.de
Anna
A
Kutschenko
Marie-Christine
MC
Reinert
Florian
F
Klinker
Walter
W
Paulus
Stefan
S
Hesse
David
D
Liebetanz
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001696:Biomechanical Phenomena; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000187:drug effects; D009128:Muscle Spasticity / Q000139:chemically induced* / Q000503:physiopathology*; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D010243:Paralysis / Q000139:chemically induced / Q000503:physiopathology; D012420:Running / Q000502:physiology*; D013744:Tetanus Toxin / Q000633:toxicity*
D013744:Tetanus Toxin; C035979:tetanospasmin; D008666:Metalloendopeptidases