A gene expression approach to mapping the functional maturation of the hippocampus

Previous studies have shown an association among seizures, neuronal death and the expression of cellular immediate-early genes (cIEG). To understand further the relationship between these processes, we investigated the ability of kainic acid (KAI) to induce behavioral responses and gene expression in the hippocampus of developing fos-lacZ transgenic mice. Despite the fact that KAI elicited seizure-like activity from P2 onwards, Fos-lacZ was first detected at P5 in CA3 pyramidal neurons. Thus, intense behavioral responses were not invariably associated with fos-lacZ expression. Furthermore, while adult CA3 neurons are highly susceptible to KAI toxicity, they are resistant at P5. Therefore, the presence of Fos-lacZ in CA3 neurons is not necessarily predictive of their fate. By P10, Fos-lacZ was induced in CA3 neurons and in the most mature granule neurons of the dentate gyrus (DG). Between P15 and P20, KAI induced fos-lacZ in all CA1 and CA3 pyramidal neurons and most granule neurons of the DG. This stereotypical pattern of fos-lacZ expression mirrors the ontogeny of hippocampal circuitry and glutamate signalling. Thus the fos-lacZ mice can be used to map the functional maturation of the nervous system with single cell resolution. The scope of this approach was extended by administration of additional chemoconvulsants to fos-lacZ mice and by analysis of fos-lacZ transgenic mice with mutations in their FAP site. These additional studies revealed anatomical and mechanistic differences in glutamate receptor-mediated transcriptional responses in the nervous system.