Phrenic, but not hypoglossal, motor output is diminished in a rat model of amyotrophic lateral sclerosis (ALS)

Abstract

ALS causes motoneuron degeneration and, ultimately, patient death by respiratory failure. We investigated the capacity to maintain respiratory motor output in a transgenic rat model of ALS that over expresses a mutated form of superoxide dismutase-1 (SOD1G93A). Phrenic and hypoglossal nerve output were recorded from anesthetized, vagotomized and ventilated end-stage SOD1G93A or wild type rats at different levels of respiratory drive regulated by controlling arterial PCO2 levels between the apneic CO2-threshold (SOD1G93A: 41±1 mmHg; wild type: 42±2 mmHg) and severe hypercapnia (90 mmHg). During baseline conditions (3 mmHg above CO2-threshold), phrenic burst amplitude was significantly less in SOD1G93A (1.2±0.2 Volts) vs wild type rats (2.8±0.4 V; p < 0.01), a relationship that persisted during hypercapnia (SOD1G93A: 2.4±0.5 V; wild type: 4.6±0.4 V; p < 0.01). Immunohistochemistry showed decreased motoneuron cell counts in the phrenic motor nucleus. In contrast, XII activity was similar in SOD1G93A and wild type rats in all conditions studied, and XII motoneuron cell counts were normal relative to wild type rats. As ventilation is normal or enhanced during hypercapnia in unanesthetized SOD1G93A rats, compensatory mechanisms preserve the capacity to breathe until late stage disease. Whereas ventilation in intact rats may not be a reliable quantitative index of respiratory compromise in this animal model, phrenic nerve recordings demonstrate clear functional impairment and may be a useful indicator of disease progression. Supported by ALS Association and NIH HL 89209, HL 65383 and HL07654.