Abstract
Preclinical diagnosis of motor neuron disease (MND) in the wobbler mouse (wr/wr) has been impossible until recently. However, with the development of a new hybrid, the C57BL/6J x New Zealand Black (B6NZB) wr/wr mouse, the polymerase chain reaction (PCR) can be used to establish the preclinical diagnosis. We compared the clinical and histological features of MND and the effects of neurotrophic factor cotreatment between the hybrid B6NZB-wr/wr and the congenic C57BL/6J-wr/wr mice. Clinical assessments of body weight, grip strength, running speed, paw position, and walking pattern were made weekly from age 2 weeks through 8 weeks (n = 10, B6NZB-wr/wr; n = 15, C57BL/6J-wr/wr). Survival was analyzed (n = 7, each strain) as was C5 and C6 spinal cord motoneuron morphology and ventral root histometry (n = 7, each strain). For cotreatment, 8 B6NZB-wr/wr and 7 C57BL/6J-wr/wr mice received subcutaneous ciliary neurotrophic factor (1 mg/kg) and brain-derived neurotrophic factor (5 mg/kg) on alternate days, 6 days/week for 4 weeks. B6NZB-wr/wr mice could be distinguished from C57BL/6J-wr/wr mice at age 3 weeks by a more abnormal paw position (P < 0.01) and walking pattern (P < 0.05) and lower grip strength (P < 0.001) and running speed (P < 0.001). After 3 weeks, the changes continued to be greater in B6NZB-wr/wr mice. Although B6NZB-wr/wr mice were more severely affected early in the disease, their survival was comparable to C57BL/6J-wr/wr mice. Anterior horn cell vacuolar degeneration and myelinated fiber histometry were similar in both strains. The clinical response to CNTF/BDNF cotreatment was marked in both groups although it was weaker in B6NZB-wr/wr mice. Thus, the hybrid B6NZB-wr/wr mice have a more severe clinical phenotype and offer a unique opportunity to study the mechanisms of presymptomatic motor neuron degeneration and the effects of therapeutic agents for human MND.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 247-255 |
| Number of pages | 9 |
| Journal | Experimental Neurology |
| Volume | 148 |
| Issue number | 1 |
| DOIs | |
| State | Published - Nov 1997 |
Funding
We greatly appreciate continuous support given by Bruce D. Trapp, Ph.D., in providing the laboratory facilities and valuable discussion. We are also grateful to Drs. F. Riéger and A. Ait-Ikhlef, INSERM, Paris, France, for supplying the glns-ps1 primers and their kind collaboration. Regeneron Pharmaceuticals (Drs. V. Wong and R. M. Lindsay) kindly provided the CNTF and BDNF. Gisela Bunge and Renata Klinkosz provided excellent technical assistant in maintaining the wobbler mouse colony. This study was funded partly by grants from the Amyotrophic Lateral Sclerosis Association (HM). TI is a research fellow funded by Sumitomo Pharmaceuticals, Japan.
ASJC Scopus subject areas
- Neurology
- Developmental Neuroscience