AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability

Area of Science:

• Neuroscience
• Neurobiology
• Cellular Neuroscience

Background:

• AMPA receptor-mediated excitotoxicity is implicated in motoneuron death in amyotrophic lateral sclerosis (ALS).
• Motoneurons exhibit greater susceptibility to AMPA receptor-mediated injury compared to other spinal neurons.
• Hypotheses suggest this vulnerability stems from highly Ca2+-permeable AMPA receptors and low expression of the GluR2 subunit.

Purpose of the Study:

• To quantify the Ca2+ permeability of AMPA receptors in motoneurons.
• To determine the fractional expression of the GluR2 subunit in motoneurons.
• To compare these properties with those of dorsal horn neurons.

Main Methods:

• Isolation and culture of rat spinal motoneurons and dorsal horn neurons.
• Whole-cell patch-clamp electrophysiology to measure Ca2+ permeability.
• Single-cell reverse transcription polymerase chain reaction (RT-PCR) to quantify GluR2 mRNA expression.

Main Results:

• Motoneurons showed significantly higher vulnerability to AMPA and kainate than dorsal horn neurons.
• All motoneurons expressed GluR2 mRNA (approx. 40% of total AMPA receptor subunit mRNA).
• Motoneuron AMPA receptors exhibited intermediate Ca2+ permeability (P(Ca2+)/P(Cs+) approx. 0.4).
• GluR2 expression and Ca2+ permeability showed greater variability in dorsal horn neurons but no significant mean difference compared to motoneurons.
• GluR2 was almost completely edited at the Q/R site in both neuron types.

Conclusions:

• The selective vulnerability of motoneurons to AMPA receptor agonists is not solely determined by the Ca2+ permeability of their AMPA receptors.
• The presence of GluR2 and intermediate Ca2+ permeability in motoneurons challenge previous hypotheses regarding their unique susceptibility.
• Further research is needed to elucidate the precise mechanisms underlying motoneuron excitotoxicity in ALS.