Variability in spinal and supraspinal respiratory motor output in a mouse model of Pompe Disease

Abstract

Pompe disease is a lysosomal storage disorder reflecting systemic acid α‐glucosidase (Gaa) deficiency. We recently reported that a murine Pompe model (the Gaa−/− mouse) shows glycogen accumulation in phrenic motoneurons, reduced breathing frequency and an apparent reduction in phrenic burst amplitude (DeRuisseau et al. PNAS, 2009). We hypothesized that alterations in the neural control of breathing in Gaa−/− mice would result in increased breath‐to‐breath variability in the timing and amplitude of efferent spinal (phrenic) and brainstem (hypoglossal, XII) signals. Neurograms recorded in anesthetized, vagotomized, and ventilated mice showed that the coefficient of variation (CV) of inspiratory duration was larger in Gaa−/− vs. B6/129 control mice (P<0.05). The burst amplitude CV for Gaa−/− mice tended to be greater for phrenic (P=0.07) and was greater for XII output (P<0.05). Additional experiments are testing the hypothesis that intraspinal delivery of the Gaa gene via adeno‐associated virus (AAV5‐GAA) mitigates glycogen accumulation and respiratory control deficits in Gaa−/− mice. Immunhistological data obtained 4–8 wks post AAV5‐GAA injection (4–6 0.5 μL injections, 4.5×1013 vg/ml) indicate Gaa expression in cervical spinal motoneurons and interneurons. We are presently evaluating the impact of the spinal injection on glycogen accumulation and ventilation.