AMPA and metabotropic excitoxicity explain subplate neuron vulnerability.
Cerebral hypoxia-ischemia results in unique patterns of injury during development owing to selective vulnerability of specific cell populations including subplate neurons. To evaluate the contribution of glutamate excitotoxicity, we studied enriched cultures of subplate neurons in comparison with cortical neurons, deriving expression profiles for glutamate receptor subunits by microarray and immunoblot. The excitotoxic potency of specific glutamate receptors was tested with selective agonists and antagonists. After 1 week in culture, subplate neurons are more sensitive to oxygen-glucose deprivation than cortical neurons, confirming in vivo observations. Subplate and cortical neurons are equally sensitive to glutamate and insensitive to NMDA. Subplate neurons are more sensitive than cortical neurons to AMPA and express twofold less GluR2. Subplate neurons express significantly more mGluR3, a receptor proposed to be protective. Despite this increased expression, group II mGluR agonists increase subplate neuron death and antagonists lessen glutamate excitotoxicity, suggesting a novel mechanism for subplate vulnerability.
Nguyen
Vien
V
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
McQuillen
Patrick S
PS
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism*; D015151:Immunoblotting; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism*
D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104723:glutamate receptor ionotropic, AMPA 3; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005947:Glucose; C104722:glutamate receptor ionotropic, AMPA 2