Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

Exposure to an Environmental Neurotoxicant Hastens the Onset of Amyotrophic Lateral Sclerosis-Like Phenotype in Human Cu2+/Zn2+ Superoxide Dismutase 1 G93A Mice: Glutamate-Mediated Excitotoxicity

“…In humans, degeneration of NXII motor neurons produces signs and symptoms collectively referred to as bulbar-onset ALS (neck and head). This form of ALS is associated with increased morbidity and mortality (Smittkamp et al, 2008). We hypothesized that the common mode of excitotoxic action of MeHg would synergize with that associated with ALS etiology to hasten development of motor dysfunction.…”

Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

“…2). These changes are the earliest potentially pathogenic events yet described in the hSOD1 G93A mouse model of FALS, occurring before motoneuron mitochondrial dysfunction (as early as P14) and caspase-1 activation (P70), onset of limb and tongue motor weakness at 2-3 months, and end-phase disease at 4.5 months (Gurney et al, 1994;Bendotti et al, 2001;Smittkamp et al, 2008). These results are consistent with the hypothesis that increased persistent Na ϩ channel activity, causing widespread hyperexcitability and enhanced synaptic activity in the developing CNS, is a possible mechanism leading to neuronal death in hSOD1 G93A mice.…”

Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

“…Progressive bulbar impairment of speech and swallowing are also frequently co-occurrences in limb-onset ALS patients (Fujimura-Kiyono et al 2011;Küh-nlein et al 2008;Weikamp et al 2012), and symptoms due to bulbar deficits are among the most distressing for ALS patients (Hillel and Miller 1989). Loss of HMs (Dal Canto and Gurney 1995;Ferrucci et al 2010) and lingual movement deficits (Smittkamp et al 2008(Smittkamp et al , 2010 are also seen in transgenic animal models of ALS; HMs from transgenic models of ALS show an early onset of hyperexcitability due to an increased persistent Na ϩ current density (van Zundert et al 2008). HMs are therefore an important motor neuron group known to be susceptible to early changes in excitability and adult demise in ALS and its transgenic models.…”