Enhanced neuronal death from focal ischemia in AMPA-receptor transgenic mice.
Excitatory amino acid (EAA) receptors play an important role in neuronal cell death in acute cerebral ischemia. Blocking the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subtype of EAA receptor has been shown to reduce cell death in global cerebral ischemia. However their role in focal stroke, although suggestive, has remained more contentious. To clarify this issue, we generated transgenic mice overexpressing the AMPA receptor (AMPAR) subunit GluR2-flip which would increase AMPAR-mediated currents. Excitatory neurons in these transgenic mice are thus predicted to be more susceptible than wild-type neurons to EAA (glutamate)-induced excitotoxic damage. Consistent with this prediction, cultured neurons from transgenic mice had a lower LD50 for exposure to glutamate (10(-3)-10(-5) M for 5 min) compared to wild-type neurons. Moreover, transgenic mice subjected to permanent focal ischemia of the middle cerebral artery (MCA) using the intralumenal filament model sustained larger infarctions compared to wild-type controls. Hence we have developed a genetic mouse model that demonstrates the crucial role of AMPAR containing GluR2-flip in the pathogenesis of focal hypoxic-ischemic neuronal cell death. This model will be a valuable tool in elucidating molecular mechanisms of glutamate excitotoxicity and evaluating the efficacy of glutamate receptor antagonists in attenuating post-ischemic neuronal cell death.
Le
D
D
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Das
S
S
Wang
Y F
YF
Yoshizawa
T
T
Sasaki
Y F
YF
Takasu
M
M
Nemes
A
A
Mendelsohn
M
M
Dikkes
P
P
Lipton
S A
SA
Nakanishi
N
N
D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D016133:Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2