Abstract
In the mSOD1 model of ALS, the excitability of motoneurons is poorly controlled, oscillating between hyperexcitable and hypoexcitable states during disease progression. The hyperexcitability is mediated by excessive activity of voltage-gated Na+ and Ca2+ channels that is initially counteracted by aberrant increases in cell size and conductance. The balance between these opposing actions collapses, however, at the time that the denervation of muscle fibers begins at about P50, resulting in a state of hypo-excitability and cell death. We propose that this process of neurodegeneration ensues from homeostatic dysregulation of excitability and have tested this hypothesis by perturbing a signal transduction pathway that plays a major role in controlling biogenesis and cell size. Our 『homeostatic dysregulation hypothesis' predicted that neonatal mSOD1 motoneurons would be much more sensitive to such perturbations than wild type controls and our results strongly support this hypothesis. Our results have important implications for therapeutic approaches to ALS.
Highlights
In the work described here, we have explored the hypothesis that neurodegeneration ensues from homeostatic dysregulation of excitability
As the animals mature (P0-P40), this surge in excitability mediated by enhanced persistent inward currents (PICs) continues[9], but is brought under control by the young adult state, probably by balancing increased PICs against an aberrant increase in cell size and electrical conductance[10,11,12,13,14,15]
The underlying premise of the present study is that during their life course, from development through senescence, neurons regulate their excitability through a host of homeostatic control mechanisms to maintain a firing rate within their optimal operational range[51,52] and that dysregulation of any of these homeostatic mechanisms produced by innate aberrancies may lead to premature cell death
Summary
In the work described here, we have explored the hypothesis that neurodegeneration ensues from homeostatic dysregulation of excitability. As the animals mature (P0-P40), this surge in excitability mediated by enhanced PICs continues[9], but is brought under control by the young adult state, probably by balancing increased PICs against an aberrant increase in cell size and electrical conductance[10,11,12,13,14,15]. This parallel, yet balanced increase in PICs and conductance may collapse at the time that the denervation of muscle fibers begins at about P50 as hypoexcitability develops[16]. These reductions were so large that the cells became completely inexcitable, strongly suggesting that the homeostatic gain in the mutant was rendered excessive and lethal
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