Respiratory Dysfunction in a Mouse Model of Spinocerebellar Ataxia 7

Abstract

Spinocerebellar ataxia type 7 (SCA‐7) is a neurodegenerative polyglutamine disease within the family of spinocerebellar ataxias. Classically SCA7 is a disease of ataxia and vision loss. However, patients with SCA also have difficulty breathing, swallowing, coughing and maintaining a stable open airway which often result in fatal respiratory failure. While respiratory measures have been reported in other SCA mouse models, ventilation in a SCA‐7 mouse has not yet been studied. Using the SCA‐7 mouse model (Atxn7266Q/+) we sought to characterize the respiratory pathology of SCA‐7.Whole body plethysmography (WBP) was used to assess respiratory dysfunction in the Atxn7266Q/+ mouse both at baseline breathing (FiO2: 0.21; nitrogen balance) and during a hypercapnic and hypoxic challenge (Fi:CO2: 0.07, FiO2: 0.10; nitrogen balance). Neurobehavioral testing and strength was assessed using the inverted screen test and the grip strength test. Post mortem histological analysis was performed on the phrenic and hypoglossal motor neurons and nerves.At 4 weeks of age, the SCA‐7 mice are indistinguishable from their unaffected littermates. However, by 8 weeks of age, SCA‐7 mice perform poorly on both neurobehavioral and strength tests as compared to their WT littermates. 50% of the SCA‐7 mice died by 9 weeks, while littermate controls thrived. SCA‐7 mice have elevated respiratory rate at baseline, as well as reduced tidal volume, minute ventilation, peak inspiratory flow, peak expiratory flow, and inspiratory time during the respiratory challenge. These results indicate that the SCA‐7 mice have respiratory dysfunction. To understand the respiratory deficits, ongoing studies are histologically analyzing the diaphragm neuromuscular junction, phrenic and hypoglossal nerves, as well as phrenic and hypoglossal motor nuclei. Preliminary nerve analysis of the hypoglossal and phrenic nerves reveals significant axonal pathology. In conclusion, WBP analysis and preliminary histological nerve data reveals respiratory dysfunction in the Atxn7266Q/+ mouse model.Support or Funding Information Funding: R01 HD099486‐01; 1R21NS098131‐01