Ventilatory impairment in the dysmyelinated Long Evans shaker rat

Abstract

Although respiratory complications significantly contribute to morbidity/mortality in advanced myelin disorders, little is known concerning mechanisms whereby dysmyelination impairs ventilation, or how patients compensate (i.e. plasticity). To establish a model for studies concerning mechanisms of ventilatory impairment/compensation, we tested the hypotheses that respiratory function progressively declines in a model of CNS dysmyelination, the Long Evans shaker rat (les). The observed impairment is associated with abnormal inspiratory neural output. Minimal myelin staining was found throughout the CNS of les rats, including the brainstem and cervical bulbospinal tracts. Ventilation (via whole-body plethysmography) and phrenic motor output were assessed in les and wild-type (WT) rats during baseline, hypoxia (11% O2) and hypercapnia (7% CO2). Hypercapnic ventilatory responses were similar in young adult les and WT rats (2 months old); in hypoxia, rats exhibited seizure-like activity with sustained apneas. However, 5–6 month old les rats exhibited decreased breathing frequencies, mean inspiratory flow (VT/TI) and ventilation (V˙E) during baseline and hypercapnia. Although phrenic motor output exhibited normal burst frequency and amplitude in 5–6 month old les rats, intra-burst activity was abnormal. In WT rats, phrenic activity was progressive and augmenting; in les rats, phrenic activity was decrementing with asynchronized, multipeaked activity. Thus, although ventilatory capacity is maintained in young, dysmyelinated rats, ventilatory impairment develops with age, possibly through discoordination in respiratory motor output. This study is the first reporting age-related breathing abnormalities in a rodent dysmyelination model, and provides the foundation for mechanistic studies of respiratory insufficiency and therapeutic interventions.