Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro.
The nonphosphorylated neurofilament marker SMI-32 stains motor neurons in spinal cord slices and stains a subset of cultured spinal neurons ["large SMI-32(+) neurons"], which have a morphology consistent with motor neurons identified in vitro: large cell body, long axon, and extensive dendritic arborization. They are found preferentially in ventral spinal cord cultures, providing further evidence that large SMI-32(+) neurons are indeed motor neurons, and SMI-32 staining often colocalizes with established motor neuron markers (including acetylcholine, calcitonin gene-related peptide, and peripherin). Additionally, choline acetyltransferase activity (a frequently used index of the motor neuron population) and peripherin(+) neurons share with large SMI-32(+) neurons an unusual vulnerability to AMPA/kainate receptor-mediated injury. Kainate-induced loss of these motor neuron markers is Ca2+-dependent, which supports a critical role of Ca2+ ions in this injury. Raising extracellular Ca2+ exacerbates injury, whereas removal of extracellular Ca2+ is protective. A basis for this vulnerability is provided by the observation that most peripherin(+) neurons, like large SMI-32(+) neurons, are subject to kainate-stimulated Co2+ uptake, a histochemical stain that identifies neurons possessing Ca2+-permeable AMPA/kainate receptor-gated channels. Finally, of possibly greater relevance to the slow motor neuronal degeneration in diseases, both large SMI-32(+) neurons and peripherin(+) neurons are selectively damaged by prolonged (24 hr) low-level exposures to kainate (10 microM) or to the glutamate reuptake blocker L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM). During these low-level kainate exposures, large SMI-32(+) neurons showed higher intracellular Ca2+ concentrations than most spinal neurons, suggesting that Ca2+ ions are also important in this more slowly evolving injury.
Carriedo
S G
SG
Department of Psychobiology, University of California-Irvine, 92717-4290, USA.
Yin
H Z
HZ
Weiss
J H
JH
D000818:Animals; D015415:Biomarkers; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D003998:Dicarboxylic Acids / Q000494:pharmacology; D005136:Eye Proteins / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology*; D008562:Membrane Glycoproteins; D051379:Mice / Q000196:embryology; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology*; D009419:Nerve Tissue Proteins; D009479:Neuropeptides / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D064531:Peripherins; D011759:Pyrrolidines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000502:physiology*; D018092:Kainic Acid Receptors / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D015415:Biomarkers; D002118:Calcium; D003998:Dicarboxylic Acids; D005136:Eye Proteins; D007381:Intermediate Filament Proteins; D007473:Ion Channels; D007608:Kainic Acid; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D014179:Neurotransmitter Uptake Inhibitors; D064531:Peripherins; D011759:Pyrrolidines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid