Age-dependent poliomyelitis in mice is associated with respiratory failureand viral replication in the central nervous system and lung

Age-dependent poliomyelitis (ADPM) is a virally induced neuroparalytic dise ase of mice and a model for amyotrophic lateral sclerosis (ALS). ADPM is tr iggered in genetically susceptible mice by immunosuppression and infection with lactate dehydrogenase-elevating virus (LDV). Both ADPM and ALS are cha racterized by progressive degeneration of anterior horn motor neurons, and death in ALS is usually associated with respiratory failure. To assess resp iratory function in ADPM, we investigated ventilation in conscious control and LDV-infected C58/J mice breathing air and then 6.5% CO2 in O-2. Three d ays after LDV infection, ventilation in response to CO2 was half of that co mpared to the uninfected state, but become normalized by 10 days. Administr ation of cyclophosphamide alone (200 mg/kg, ip), an immunosuppressant, had no effect on ventilation. Induction of ADPM by concomitant administration o f LDV to cyclophosphamide-treated mice resulted in altered gait, hindlimb p aralysis, wasting, decreased metabolism, and decreased body temperature by 4 degreesC relative to controls, Compared to baseline values, mice with ADP M had decreased tidal volume and ventilation while breathing air, and while exposed to the CO2 challenge they were unable to increase tidal volume, fr equency of breathing, or ventilation. Using in situ hybridization, LDV repl ication was noted within the spinal cord, brain, and lung, but not in the d iaphragm, Thus, respiratory failure is a contributory mechanism leading to death in ADPM and is associated with LDV replication in the CNS and lung. T his animal model may be useful to investigate physiological and molecular m echanisms associated with the development of respiratory failure in neurode generative diseases.