Seizures induced by fever are the most prevalent age-specific seizures in infants and young children. Whether they result in long-term sequelae such as neuronal loss and temporal lobe epilepsy is controversial. Prospective studies of human febrile seizures have found no adverse effects on the developing brain. However, adults with temporal lobe epilepsy and associated limbic cell loss frequently have a history of prolonged febrile seizures in early life. These critical issues may be resolved using appropriate animal models. Published models of hyperthermic seizures have used 'adolescent' and older rats, have yielded a low percentage of animals with actual seizures, or have suffered from a high mortality, rendering them unsuitable for long-term studies. This article describes the establishment of a model of febrile seizures using the infant rat. Hyperthermia was induced by a regulated stream of mildly heated air, and the seizures were determined by both behavioral and electroencephalographic (EEG) criteria. Stereotyped seizures were generated in 93.6% of 10-11-day-old rats. EEG correlates of these; seizures were not evident in cortical recordings, but were clearly present in depth recordings from the amygdala and hippocampus. Prolonged febrile seizures could be induced without bums, yielding a low mortality (11%) and long-term survival. In summary, an infant rat paradigm of EEG-confirmed, hyperthermia-induced seizures which is suitable for long-term studies is described. This model should be highly valuable for studying the mechanisms and sequelae of febrile seizures.

Corticotropin releasing hormone (CRH) has been localized to interneurons of the mammalian cerebral cortex, but these neurons have not been fully characterized. The present study determined the extent of colocalization of CRH with glutamate decarboxylase (GAD) and calcium-binding proteins in the infant rat neocortex using immunocytochemistry. CRH-immunoreactive (ir) neurons were classified into two major groups. The first group was larger and consisted of densely CRH-immunostained small bipolar cells, predominantly localized to layers II and III. The second group of CRH-ir cells was lightly labeled and included multipolar neurons mainly found in deep cortical layers. Co-localization studies indicated that the vast majority of CRH-ir neurons, including both bipolar and multipolar types, was co-immunolabeled for GAD-65 and GAD-67. Most multipolar, but only some bipolar, CRH-ir neurons also contained parvalbumin, while CRHir neurons rarely contained calbindin or calretinin. These results indicate that virtually all CRH-ir neurons in the rat cerebral cortex are GABA-ergic. Furthermore, since parvalbumin is expressed by cortical basket and chandelier cells, the colocalization of CRH and parvalbumin suggests that some cortical CRH-ir neurons may belong to these two cell types.

Adrenalectomy in the mature rat leads to death of granule cells in the dentate gyrus of the hippocampal formation. The mechanisms underlying this cell death have not been fully clarified: It has been considered that the granule cells require adrenal steroids for their survival, since corticosterone replacement prevents their death. However, adrenalectomy-induced loss of negative feedback also increases levels of corticotropin releasing hormone (CRH) in several limbic brain regions. CRH is known to induce neuronal death in hippocampal regions rich in CRH receptors. This study tested the hypothesis that adrenalectomy-induced granule cell death is mediated via the enhanced activation of CRH receptors. The extent of granule cell degeneration was compared among 4 groups of young adult male rats: Sham-adrenalectomy controls, adrenalectomized rats, adrenalectomized rats infused with a CRH antagonist from the onset of steroid deprivation to the time of sacrifice, and adrenalectomized rats infused with vehicle only. (9-41)-alpha-helical CRH was administered using an osmotic pump into the cerebral ventricles. Adrenalectomy led to robust granule cell degeneration, which was maximal in the suprapyramidal blade of the dentate gyrus. Infusion of the CRH antagonist in doses shown to block CRH actions on limbic neurons did not decrease the number of degenerating granule cells compared with the untreated or vehicle-infused adrenalectomized groups. Therefore, blocking the actions of CRH does not prevent adrenalectomy-induced granule cell death, consistent with a direct effect of corticoids on the survival of these neurons.