Kainic acid-induced neuronal death is associated with DNA damage and a unique immediate-early gene response in c-fos-lacZ transgenic rats

Gary M. Kasof, Allan Mandelzys, Shanna D. Maika, Robert E. Hammer, Tom Curran, James I. Morgan

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

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 (cI0EGs) following KA or pentylenetetrazol (PTZ) treatment in c-fos-lacZ transgenic rate. 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, β- 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.

Original languageEnglish (US)
Pages (from-to)4238-4249
Number of pages12
JournalJournal of Neuroscience
Volume15
Issue number6
DOIs
StatePublished - 1995

Keywords

  • TUNEL
  • excitotoxicity
  • fos
  • jun
  • kainic acid
  • oxidative stress
  • pentylenetetrazol

ASJC Scopus subject areas

  • Neuroscience(all)

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