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

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 (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.

Absence of a Persistently Elevated 37 kDa Fos-Related Antigen and AP-1-Like DNA-Binding Activity in the Brains of Kainic Acid-TreatedfosB Null Mice

“…Recent studies demonstrated the protracted expression of AP-1-like DNA-binding activity in the rat brain after chronic cocaine administration, electroconvulsive shock, and drug-induced seizure activity (Hope et al, 1992(Hope et al, , 1994aKaminska et al, 1994;Pennypacker et al, 1994;Kasof et al, 1995). Figure 1A shows that this phenomenon also occurs in the mouse.…”

“…Although this is theoretically possible, multiple probes from different regions of the fosB mRNA fail to detect additional transcripts by in situ hybridization and Northern blotting (Fig. 5) (Z erial et al, 1989;Nakabeppu and Nathans, 1991;Kaminska et al, 1994;Chen et al, 1995;Kasof et al, 1995). Therefore, the most likely explanation is that the 37 kDa ⌬-FosBlike protein has a very long half-life.…”

“…Repetitive electroconvulsive seizures, chronic treatment with certain drugs of abuse or induction of status epilepticus with kainic acid lead to a persistent increase in AP-1-like DNAbinding activity in the brain (Hope et al, 1992(Hope et al, , 1994aPennypacker et al, 1994;Kasof et al, 1995). Moreover, based upon supershift and immunoblot analyses, these AP-1 complexes appear to be heterodimers of JunD in association with a series of proteins in the range of 35-37 kDa that cross-react with antisera to FosB (Hope et al, 1994b;Chen et al, 1995).…”

“…While these proteins have physical and immunological properties consistent with the splice variant of FosB, termed ⌬-FosB (Dobrzanski et al, 1991;Mumberg et al, 1991;Nakabeppu and Nathans, 1991;Yen et al, 1991), their precise identity remains uncertain. Some of this ambiguity stems from the fact that while fosB mRNA is induced during the acute response to a stimulus, it is not chronically elevated (Chen et al, 1995;Kasof et al, 1995). One means of determining the molecular identity of the ⌬-FosB-like material and assessing its possible physiological significance is through the analysis of fosB-null mice.…”

Novel Mouse Model of Monocular Amaurosis Fugax

“…19 However, c-fos expression is also seen in neurons committed to apoptosis. 20 The c-jun gene has been linked to neuronal apoptosis 21 and neuronal rescue. 6 Ischemia also upregulates Cox-2 expression; we observed a peak at 1 hour and continued strong expression at 4 hours.…”