| SOD1-G93A transgenic mice are widely used as an animal model of amyotrophic lateral sclerosis (ALS) for the purpose of understanding the pathogenesis of this fatal disease in humans as well as investigating potential treatments. Virtually all humans with ALS develop swallowing impairment (dysphagia) affecting the oral and pharyngeal stages of swallowing. Dysphagia in ALS typically results in respiratory complications and severe weight-loss, both of which are associated with death in this patient population. It is unknown whether SOD1-G93A transgenic mice develop characteristics of dysphagia similar to humans with this disease. To test this hypothesis, a battery of behavioral tests and electrophysiological and histological methods were performed on SOD1-G93A transgenic mice. Age-matched wild-type (WT) littermates served as controls. Assessment of the oral stage of swallowing entailed video recording and analysis of 60 animals (30 WT, 30 transgenic) at three time points [pre-disease (60 days), disease onset (∼110 days), and disease end-stage (∼140 days)] to determine the mean lick and mastication rates for each animal over time. At the final time point, histological analysis was conducted on two brainstem motor nuclei: trigeminal (innervates the muscles of mastication) and hypoglossal (innervates the tongue). Lick and mastication rates were significantly lower (p<0.05) for transgenic mice as compared with controls at each time point, thereby demonstrating that SOD1-G93A mice develop symptoms of oral stage dysphagia that can be detected at 60 days of age and progressively worsen as the disease advances. Moreover, evidence of neurodegeneration (i.e., vacuolation) was found in the trigeminal and hypoglossal nuclei, thus establishing a clinico-pathological correlation of oral dysphagia in SOD1-G93A transgenic mice. To investigate the pharyngeal stage of swallowing, electrical stimulation was applied to the intact superior laryngeal nerve (SLN) of 21 mice (12 WT, 9 transgenic) using a constant current and stimulus width at four frequencies (10, 20, 30, 40 Hz). The optimal stimulus frequency to evoke swallowing was two-fold higher in transgenic mice (both sexes) as compared to WT mice, and the lowest stimulus frequency to evoke swallowing was significantly higher (p<0.05) for transgenic females, as compared to transgenic males and WT controls. Histological analysis revealed evidence of neurodegeneration within the representative motor (nucleus ambiguus; vacuoles and SOD1 aggregates) and sensory (nodose ganglion; SOD1 aggregates) components of the pharyngeal stage of swallowing for both male and female transgenic mice. This finding suggests that pharyngeal dysphagia in ALS may be attributed to both motor and sensory pathology; therefore, additional testing of this hypothesis is warranted. Overall, the SOD1-G93A transgenic mouse displays characteristics of oral and pharyngeal dysphagia similar to humans with ALS. Therefore, the SOD1-G93A transgenic mouse is a promising model of dysphagia for use in translational research to benefit humans with this disease. |
