Respiratory motoneurons and pathological conditions: Lessons from hypoglossal motoneurons challenged by excitotoxic or oxidative stress

Hypoglossal motoneurons (HMs) are respiration-related brainstem neurons that command rhythmic contraction of the tongue muscles in concert with the respiratory drive. In experimental conditions, HMs can exhibit a range of rhythmic patterns that may subserve different motor outputs and functions. Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS; Lou-Gehrig disease) often damage HMs with distressing symptoms like dysarthria, dysphagia and breathing difficulty related to degeneration of respiratory motoneurons. While the cause of ALS remains unclear, early diagnosis remains an important goal for potential treatment because fully blown clinical symptoms appear with degeneration of about 30% motoneurons. Using a simple in vitro model of the rat brainstem to study the consequences of excitotoxicity or oxidative stress (believed to occur during the onset of ALS) on HMs, it is possible to observe distinct electrophysiological effects associated with HM experimental pathology. In fact, excitotoxicity caused by glutamate uptake block triggers sustained bursting and enhanced synaptic transmission, whereas oxidative stress generates slow depolarization, augmented repeated firing, and decreased synaptic transmission. In either case, only a subpopulation of HMs shows abnormal functional changes. Although these two insults induce separate functional signatures, the consequences on HMs after a few hours are similar and are preceded by activation of the stress transcription factor ATF-3. The deleterious action of excitotoxicity is inhibited by early administration of riluzole, a drug currently employed for the symptomatic treatment of ALS, demonstrating that this in vitro model can be useful for testing potential neuroprotective agents.