AMPA receptor current density, not desensitization, predicts selective motoneuron vulnerability.
Spinal motoneurons are more susceptible to AMPA receptor-mediated injury than are other spinal neurons, a property that has been implicated in their selective degeneration in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether this difference in vulnerability between motoneurons and other spinal neurons can be attributed to a difference in AMPA receptor desensitization and/or to a difference in density of functional AMPA receptors. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. Single-cell RT-PCR quantification of the relative abundance of the flip and flop isoforms of the AMPA receptor subunits, which are known to affect receptor desensitization, did not reveal any difference between the two cell populations. Examination of AMPA receptor desensitization by patch-clamp electrophysiological measurements on nucleated and outside-out patches and in the whole-cell mode also yielded similar results for the two cell groups. However, AMPA receptor current density was two- to threefold higher in motoneurons than in dorsal horn neurons, suggesting a higher density of functional AMPA receptors in motoneuron membranes. Pharmacological reduction of AMPA receptor current density in motoneurons to the level found in dorsal horn neurons eliminated selective motoneuron vulnerability to AMPA receptor activation. These results suggest that the greater AMPA receptor current density of spinal motoneurons may be sufficient to account for their selective vulnerability to AMPA receptor agonists in vitro.
Vandenberghe
W
W
Department of Neurology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois 60637, USA.
Ihle
E C
EC
Patneau
D K
DK
Robberecht
W
W
Brorson
J R
JR
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001569:Benzodiazepines / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology
D001581:Benzothiadiazines; D018691:Excitatory Amino Acid Antagonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D018091:Receptors, AMPA; D001569:Benzodiazepines; C079692:GYKI 53655; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C004639:cyclothiazide; D007608:Kainic Acid