Excitability Dysfunction Mechanisms Underlying the TDP43-Dependent ALS and FTD Pathogenesis - Project Summary/Abstract Despite much effort to identify mechanisms underlying amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration dementia (FTLD or FTD), effective treatments remain elusive. Motoneuron (MN) excitability dysfunction remains the most tightly linked to ALS disease pathology. Much research has reported on disease alterations in the excitability mechanisms of MNs. However, these data often conflict, as hyperexcitability, hypoexcitability, and normal excitability have all been seen in animal models of ALS. Such inconsistent data obscure the role of these excitability changes (i.e., neuroprotective or detrimental). Most of these conflicting reports are seen in mutant super-oxide dismutase (SOD) models of ALS, the most commonly studied mouse model of ALS. Our data obtained (via our active grant) from the aggressive G93A SOD mouse model of ALS suggests that both hypo- and hyperexcitability disease changes might take place concurrently within diseased MNs. Here, we propose to examine a recent, novel rNLS8 mouse model that recapitulates pathologic Transactive-response DNA-binding Protein 43 (TDP43) inclusions seen in upper and lower MNs in >90% of ALS patients, leading to neuronal loss in the brain and spinal cord. TDP43 is specifically seen in most sporadic-onset ALS cases; thus, between them, the G93A and rNLS8 models represent most ALS, and also FTD, cases. However, to date, excitability dysregulation has not been examined in this model. Thus, our objective is to characterize the novel rNLS8 TDP43 mouse model of ALS and compare this data to our existing data from G93A mice. Both models demonstrate very different disease scenario and progression, yet ultimately both lead to MN loss and death. By comparing and contrasting mechanisms of excitability dysregulation between these models, we expect to parse the roles that individual alterations play in ALS/FTD disease pathology via 3 Specific Aims: Aim 1: Determine MN and synaptic excitability in the rNLS8 model. It is currently unknown whether MN excitability is altered in the rNLS8 model – as in other ALS models – and whether synaptic excitability dysfunction is also involved. Thus, we will measure intrinsic MN and synaptic excitability in the rNLS8 model via electrophysiology recordings, at early, middle, and late disease stages, then contrast them to G93A data. Aim 2: Determine the roles of ion channels and synaptic inputs in the death of spinal MNs in rNLS8 mice. We will measure expression levels of ion channels and synapses in spinal MNs of rNLS8 mice at early, middle, and late disease stages, then contrast them to G93A data. Aim 3: Determine the roles of ion channels & synaptic inputs in the death of cortical neurons in rNLS8 mice. Loss of cortical neurons in rNLS mice recapitulates key aspects of ALS-comorbid FTD. To examine if excitability mechanisms involved in the death of spinal MNs are also involved in FTD dementia, we will measure expression levels of ion channels and synapses in cortical/subcortical neurons of rNLS8 mice at early, mid, and late disease stages.
