Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused 
by dysfunction and degeneration of motor neurons starting in adulthood. Most of 
our knowledge about the pathophysiological mechanisms of ALS comes from 
transgenic mice models that emulate a subgroup of familial ALS cases (FALS), 
with mutations in the gene encoding superoxide dismutase (SOD1). In the more 
than 15 years since these mice were generated, a large number of abnormal 
cellular mechanisms underlying motor neuron degeneration have been identified, 
but to date this effort has led to few improvements in therapy, and no cure. 
Here, we consider that this surfeit of mechanisms is best interpreted by current 
insights that suggest a very early initiation of pathology in motor neurons, 
followed by a diversity of secondary cascades and compensatory mechanisms that 
mask symptoms for decades, until trauma and/or aging overloads their protective 
function. This view thus posits that adult-onset ALS is the consequence of 
processes initiated during early development. In fact, motor neurons in neonatal 
mutant SOD mice display important alterations in their intrinsic electrical 
properties, synaptic inputs and morphology that are accompanied by subtle 
behavioral abnormalities. We consider evidence that human mutant SOD1 protein in 
neonatal hSOD1(G93A) mice instigates motor neuron degeneration by increasing 
persistent sodium currents and excitability, in turn altering synaptic circuits 
that control excessive motor neuron firing and leads to excitotoxicity. We also 
discuss how therapies that are aimed at suppressing abnormal neuronal activity 
might effectively mitigate or prevent the onset of irreversible neuronal damage 
in adulthood. J. Cell. Biochem. 113: 3301-3312, 2012. © 2012 Wiley Periodicals, 
Inc.