Multiple mechanisms has been proposed for the selective vulnerability of motoneurons in neurodegenerative diseases. In reflecting on the prior work from our laboratories, as well as that of our colleagues around the world, we have developed a synthetic hypothesis that accounts for a vast majority of the reported findings. We propose that the net response of mouse motoneurons to the presence of mutant proteins is a disregulation of homeostatic plasticity. This manifests as an increased `gain' of both the up- and down-regulation of compensatory mechanisms designed to control the level of motoneuronal activity. The toxic increase of gain function leads to overcompensation and a dramatic cascade of homeostatic oscillations that increases motoneuron morbidity. Further, we propose that size-scaling of these compensatory mechanisms leads to the observed greater vulnerability of the largest motoneurons. The goal of this project is to provide rigorous testing of this novel disregulation hypothesis using mutant SOD1 mice as a model system for neurodegenerative diseases that disproportionately target motoneurons. The proposed experiments rest heavily on our recent technical breakthroughs that enable us to perform intracellular recordings of mouse motoneurons throughout disease progression, from neonate through adult, using both in vivo and in vitro preparations, as well as our expertise in assessing the density and spatial distributions of membrane channels in motoneurons. Our approach entails presenting a series of `homeostatic challenges' to motoneuron excitability and comparing the compensatory responses of mSOD1 motoneurons to those of wild-type controls. If our hypothesis is correct, we expect to observe that mSOD1 motoneurons exhibit consistently greater responses to each of the challenges than do wild-types and that these mSOD1 responses scale with motoneuron size. There are three specific aims: to assess the responses of mSOD1 and control motoneurons to drug perturbations that alter the intrinsic electrical properties of motoneurons (Aim 1), the synaptic inputs to motoneurons (Aim 2) and the neuromodulatory inputs to motoneurons (Aim 3). The resulting data will provide a strong impetus for pursuing radical, novel therapeutic strategies as well as for elucidating the specific signal transduction cascades underlying the different homeostatic mechanisms.
Many cellular functions are disrupted in ALS. We propose this complexity arises from a single mechanism, dysregulation of homeostatic plasticity in motoneurons. We systematically test this novel concept by assessing the response of ALS and control motoneurons to homeostatic challenges, with a goal of providing a basis for new therapeutic approaches.
