Kainic acid-induced neuronal death is associated with DNA damage and a unique immediate-early gene response in c-fos-lacZ transgenic rats.
Previously, we established that persistent upregulation of c-fos expression preceded kainic acid (KA)-induced neuronal death in mice. To discriminate between events that are products of the seizures elicited by KA and those that are specifically associated with its neurotoxic actions, we have examined the expression of cellular immediate-early genes (cIEGs) following KA or pentylenetetrazol (PTZ) treatment in c-fos-lacZ transgenic rats. While both chemoconvulsants elicit seizures, only KA causes selective neuronal death. Following treatment of transgenic rats with KA there was a protracted expression of Fos-lacZ that lasted for 2-3 d. In contrast, PTZ elicited a transient increase in the transgene product that lasted about 6 hr. Normally, Fos and Fos-lacZ were detected only in neuronal nuclei. However, 6 hr following kainic acid (but not PTZ) administration, beta-galactosidase activity appeared in the cytoplasm of neurons within vulnerable regions (as determined by the terminal transferase biotinylated-UTP nick end labeling (TUNEL) procedure). Like c-fos, transcripts for other cIEGs were elevated for longer periods in the KA-treated rat hippocampus. In addition, fra-1 and fra-2 were only induced in the KA-treated rat. These changes in mRNA levels were paralleled by a sustained increase in AP-1 DNA binding activity. Thus, quantitative and qualitative changes in AP-1 DNA binding complexes accompany neurotoxic cell death that are not observed following seizures.
Kasof
G M
GM
Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey 07710, USA.
Mandelzys
A
A
Maika
S D
SD
Hammer
R E
RE
Curran
T
T
Morgan
J I
JI
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D016923:Cell Death / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000235:genetics*; D016762:Genes, fos; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D010433:Pentylenetetrazole / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D001616:beta-Galactosidase / Q000096:biosynthesis
D009838:Oligodeoxyribonucleotides; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D001616:beta-Galactosidase; D007608:Kainic Acid; D010433:Pentylenetetrazole