GENETIC TRANSFER OF THE WOBBLER GENE TO A C57BL 6J X NZB HYBRID STOCK- NATURAL-HISTORY OF THE MOTOR-NEURON DISEASE AND RESPONSE TO CNTF AND BDNF COTREATMENT/

Preclinical diagnosis of motor neuron disease (MND) in the wobbler mou se (wr/wr) has been impossible until recently. However, with the devel opment 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 t he preclinical diagnosis. We compared the clinical and histological fe atures of MND and the effects of neurotrophic factor cotreatment betwe en the hybrid B6NZB-wr/wr and the congenic C57BL/6j-wr/wr mice. Clinic al assessments of body weight, grip strength, running speed, paw posit ion, and walking pattern were made weekly from age 2 weeks through 8 w eeks (n = 10, B6NZB-wr/wr; n = 15, C57BL/6j-wr/wr), Survival was analy zed (n = 7, each strain) as was C5 and C6 spinal cord motoneuron morph ology and ventral root histometry (n = 7, each strain). For cotreatmen t, 8 B6NZB-wr/wr and 7 C57BL/6J-wr/wr mice received subcutaneous cilia ry 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 mic e 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) a nd lower grip strength (P < 0.001) and running speed (P < 0.001). Afte r 3 weeks, the changes continued to be greater in B6NZB-wr/wr mice. Al though B6NZB-wr/wr mice were more severely affected early in the disea se, their survival was comparable to C57BL/6J-wr/wr mice, Anterior hor n cell vacuolar degeneration and myelinated fiber histometry were simi lar in both strains. The clinical response to CNTF/BDNF cotreatment wa s marked in both groups although it was weaker in B6NZB-wr/wr mice. Th us, the hybrid B6NZB-wr/wr mice have a more severe clinical phenotype and offer a unique opportunity to study the mechanisms of presymptomat ic motor neuron degeneration and the effects of therapeutic agents for human MND. (C) 1997 Academic Press.