The lithium-pilocarpine model of status epilepticus (SE) was used to study the type and distribution of seizure-induced neuronal injury in the rat and its consequences during development. Cell death was evaluated in hematoxylin- and eosin-stained sections and by electron microscopy. Damage to the CA1 neurons was maximal in the 2- and 3-week-old pups and decreased as a function of age. On the other hand, damage to the hilar and CA3 neurons was minimal in the 2-week-old rat pups but reached an adult-like pattern in the 3-week-old animals, and damage to amygdalar neurons increased progressively with age. The 3-week-old animals also demonstrated vulnerability of the dentate granule cells. To evaluate neuronal apoptosis, we used terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) stain, confocal fluorescence microscopy of ethidium bromide-stained sections, electron microscopy, and DNA electrophoresis. Neurons displaying all of those features of apoptotic death in response to SE were seen in the CA1 region of the 2-week-old pups and in the hilar border of the dentate granule cells of the 3-week-old animals. Some (3/11) of the animals that underwent SE at 2 weeks of age and most of the animals that underwent SE at 3 or 4 weeks of age (8/11 and 6/8, respectively) developed spontaneous seizures later in life; the latter showed SE-induced synaptic reorganization as demonstrated by Timm methodology. These results provide strong evidence for the vulnerability of the immature brain to seizure-induced damage, which bears features of both necrotic and apoptotic death and contributes to synaptic reorganization and the development of chronic epilepsy.

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Numerous genetic studies have shown that the CREB-binding protein (CBP) is an essential component of long-term memory formation, through its histone acetyltransferase (HAT) function. E1A-binding protein p300 and p300/CBP-associated factor (PCAF) have also recently been involved in memory formation. By contrast, only a few studies have reported on acetylation modifications during memory formation, and it remains unclear as to how the system is regulated during this dynamic phase. We investigated acetylation-dependent events and the expression profiles of these HATs during a hippocampus-dependent task taxing spatial reference memory in the Morris water maze. We found a specific increase in H2B and H4 acetylation in the rat dorsal hippocampus, while spatial memory was being consolidated. This increase correlated with the degree of specific acetylated histones enrichment on some memory/plasticity-related gene promoters. Overall, a global increase in HAT activity was measured during this memory consolidation phase, together with a global increase of CBP, p300, and PCAF expression. Interestingly, these regulations were altered in a model of hippocampal denervation disrupting spatial memory consolidation, making it impossible for the hippocampus to recruit the CBP pathway (CBP regulation and acetylated-H2B-dependent transcription). CBP has long been thought to be present in limited concentrations in the cells. These results show, for the first time, that CBP, p300, and PCAF are dynamically modulated during the establishment of a spatial memory and are likely to contribute to the induction of a specific epigenetic tagging of the genome for hippocampus-dependent (spatial) memory consolidation. These findings suggest the use of HAT-activating molecules in new therapeutic strategies of pathological aging, Alzheimer's disease, and other neurodegenerative disorders.