Disease Mechanisms
ALS is primarily characterized by the progressive loss of which cell types?
Upper and lower motorneurons
What circuit component can a Ca²⁺ channel be?
Field effect transistors/voltage controlled switch.
What is the primary role of voltage-gated K⁺ channels during an action potential?
Repolarization of the membrane
Which subunit makes AMPA receptors Ca²⁺ impermeable?
GluA2
How does Riluzole work (in part)?
Inhibits sodium channels / reduces glutamate excitotoxicity
Which ion is poorly regulated in ALS pathology?
Calcium (Ca²⁺)
Which clinical symptom reflects axonal hyperexcitability?
Fasciculations (muscle twitching)
What is the purpose of Na⁺ channels?
Depolarization & firing
What is the function and name of GluA2?
Glutamate Receptor AMPA 2 and it changes the permeability of Ca²⁺ channels.
Why are large alpha-motoneurons more vulnerable?
Higher metabolic demand and greater excitability burden
Oxidative stress affects ion channels by what mechanism?
Oxidative modification of channel proteins (altering gating/kinetics)
Which sodium current regulates subthreshold potential and repetitive firing?
Persistent sodium current
What sodium channel change drives hyperexcitability in ALS models?
Increased persistent Na⁺ current or altered activation/inactivation
What process is impaired in sporadic ALS leading to Ca²⁺-permeable AMPA receptors?
RNA editing of GluA2 (Q/R site editing)
What is the effect of Retigabine on ALS motoneurons?
Reduces hyperexcitability (via K⁺ channel activation)
What does “multifactorial nature” of ALS imply?
Multiple interacting mechanisms (genetic, excitotoxic, oxidative, etc.) drive disease
What does a prolonged strength-duration time constant indicate?
Increased persistent Na⁺ conductance / membrane hyperexcitability
What happens to N-type HVA Ca²⁺ currents in SOD1 models?
They are increased
How do AMPA receptors change during early development?
They become less Ca²⁺ permeable (increase GluA2 incorporation)
What excitability pattern is seen in iPSC ALS motoneurons over time?
Early hyperexcitability followed by later hypoexcitability
Why might hypoexcitability appear in late-stage ALS models?
Degeneration, ion channel loss, or compensatory downregulation reducing firing
A hyperpolarizing shift in Na⁺ channel activation causes what?
Channels open more easily → increased excitability
What is the function of persistent Ca²⁺ currents?
Sustained depolarization and facilitation of repetitive firing
What are AMPA receptors responsible for?
fast excitatory transmission in the central nervous systems
True or False: Hyperexcitability is universal in adult ALS mouse models
False