Ca2+-permeable AMPA receptors and selective vulnerability of motor neurons

To evaluate the role of excitotoxicity in the pathogenesis of amyotrophic l ateral sclerosis (ALS), we compared the sensitivity of motor neurons and th at of dorsal horn neurons to kainic acid (KA). Short exposure to KA resulte d in the death of motor neurons, while dorsal horn neurons were unaffected. This selective motor neuron death was completely dependent on extracellula r Ca2+ and insensitive to inhibitors of voltage-operated Ca2+ or Na+ channe ls. It was also completely inhibited by the specific AMPA antagonist LY3001 64 and by Joro spider toxin (JSTx), a selective blocker of AMPA receptors t hat lack the edited GluR2 subunit. KA selectively killed those motor neuron s that stained positive for the Co2+ histochemical staining, a measure for the presence of Ca2+-permeable AMPA receptors. These results suggest that C a2+ entry via Ca2+-permeable AMPA receptors is responsible for the selectiv e motor neuron death. As the Ca2+ permeability of the AMPA receptor is regu lated by its GluR2 subunit, we stained motor neurons for GluR2. Immunoreact ivity was present in all motor neurons, albeit to a variable degree. Howeve r, double-staining experiments demonstrated that motor neurons clearly expr essing GluR2, also expressed Ca2+-permeable AMPA receptors. This indicates that despite the abundant expression of GluR2, this subunit is excluded fro m a subset of AMPA receptors and that the activation of these receptors is responsible for the selective motor neuron death. (C) 2000 Elsevier Science B.V. All rights reserved.