A 72 kDa heat shock protein is protective against the selective vulnerability of CA1 neurons and is essential for the tolerance exhibited by CA3 neurons in the hippocampus.
The correlation between the expression of a 72 kDa heat shock protein and vulnerability of hippocampal CA1, CA3, and dentate gyrus regions to glutamate toxicity was investigated using a highly specific antisense oligonucleotide technique. Glutamate (1 mM, 15 min) caused region-dependent neuronal damage in cultured hippocampal slices 24 h after exposure and the most severe damage was observed in CA1. When slices were heat-shocked (43.5 degrees C, 30 min) before exposure to glutamate, neuronal damage in CA1 was attenuated. The strongest protection was observed when the interval between the heat shock and the exposure to glutamate was 3 days, which coincided with the maximal induction of a 72 kDa heat shock protein in neurons. When the expression of a 72 kDa heat shock protein was suppressed by the antisense oligonucleotide, the protective effect of the heat shock was completely inhibited. Glutamate itself also induced a 72 kDa heat shock protein in neurons, region-dependently, 24 h after the exposure. The signal of a 72 kDa heat shock protein in CA3 and dentate gyrus was significantly stronger than that in CA1. When the antisense oligonucleotide was applied, the damage in CA3 and dentate gyrus was exaggerated dose-dependently, and this effect was more remarkable in CA3 than in the dentate gyrus. Based on these data, we concluded that: (i) a 72 kDa heat shock protein has a protective effect against the selective vulnerability of CA1 neurons, (ii) a 72 kDa heat shock protein is an essential factor for the tolerance exhibited by CA3 neurons, and (iii) dentate gyrus tolerance is based on mechanisms other than those mediated through a 72 kDa heat shock protein.
Sato
K
K
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan. kasato@nihs.go.jp
Matsuki
N
N
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009924:Organ Culture Techniques; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000378:metabolism* / Q000503:physiopathology
D018840:HSP70 Heat-Shock Proteins; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D018698:Glutamic Acid