Animal studies have demonstrated that there are significant differences between the type and extent of seizure-induced brain damage in young and adult animals. Although seizures can induce changes in multiple areas of the brain, the hippocampus has been particularly well studied. In addition to its importance in memory and learning, the anatomy and physiology of the hippocampus are well known, making this neuronal structure an ideal focus of study.
In the adult animal, status epilepticus causes neuronal loss in hippocampal fields CA-1, CA-3, the dentate granule cell layer, and the dentate hilus.29-31 If sufficiently long, a seizure probably can result in damage at any age,32,33 but a single, prolonged seizure in an immature animal results in less cell loss.34-40
In addition to the cell loss, prolonged seizures can cause synaptic reorganization with aberrant growth (sprouting) of granule cell axons (the so-called mossy fibers) in the supragranular zone of the fascia dentata41,42 and the infrapyramidal region of CA-3.42 Seizures also activate the trk subtype of neurotrophin receptor in the mossy fiber pathway43 and alter the expression of certain glutamate subreceptors.44 Because the mossy fibers develop primarily in the early postnatal period, the development of these axons may be particularly prone to seizure-induced changes.
In studies from our laboratory,45 we evaluated the effects on synaptic reorganization of seizures induced by kainic acid (KA) during development, using the expression of growth-associated protein-43 (GAP-43), a marker for synaptogenesis, and the Timm stain, which detects the presence of zinc in granule cell axons.
Age-specific doses of KA, a glutamate agonist and potent convulsant, were used to induce seizures of similar intensity in rats varying in age from postnatal day 12 (P12) to P60. Until age P25, no differences were noted in either Timm or GAP-43 staining between animals with KA seizures and control animals. In KA-treated rats aged P25 and older, Timm staining was found in the supragranular layer of the dentate gyrus. This staining increased with age at the time of KA injection. KA-treated adult rats (P60) also exhibited increased staining in the suprapyramidal layer of the CA-3 subfields, but younger rats did not.
Changes in GAP-43, the marker for synaptogenesis, were delayed as compared to the Timm staining, with no differences between KA-treated animals and controls until age P35, when a band of GAP-43 immunostaining appeared in the supragranular inner molecular layer, progressively increasing in intensity and thickness over time.
This study confirmed the observations of Sperber et al.,46 that the degree of sprouting after status epilepticus is age-related. Why status epilepticus does not result in detectable synaptic reorganization in rats younger than P25 is not clear, but these findings suggest that reactive synaptogenesis benefits from a mature neuronal circuit in the hippocampus. By P21-P25, an adult pattern of mossy terminals has developed47 and, by P21, the adult pattern of GAP-43 immunostaining has been achieved, as demonstrated in this study. Only after these adult levels are reached does seizure-induced reactive synaptogenesis occur. Like cell loss, mossy fiber changes after seizures clearly are age-related, with younger animals demonstrating less sprouting than older animals after experiencing seizures of similar intensity.
Behavioral consequences after status epilepticus also are related to the age of the animal at the time of the status: Adult animals surviving status epilepticus show deficits in learning, memory, and behavior,38 whereas young rats experiencing status epilepticus experience fewer such deficits.38,48 Likewise, spontaneous recurrent seizures after status epilepticus are more likely to occur in adult animals than in young animals.39,49,50
Multiple reasons may exist for the age-related differences in seizure-induced damage after status epilepticus. Cellular damage occurs from excessive excitatory neurotransmitter release, which activates NMDA receptors, thereby allowing calcium to enter the cell. Calcium results in a cascade of biochemical changes that eventually result in cell death.51 The immature brain appears to be more "resistant" to the effects of glutamate than does the mature brain.52-55 Marks et al.55 found that the degree of calcium entry into the hippocampal subfield CA-1 and subsequent damage was directly related to age. In P1-P3 neurons, glutamate increased intracellular calcium minimally, whereas in P21-P25 neurons, glutamate resulted in marked increases in intracellular calcium and caused considerable swelling, blebbing, and retraction of dendrites into the soma of the neuron.
The immaturity of the neuronal network also may provide the immature brain with some protection. As noted earlier, reactive synaptogenesis of the mossy fibers appears to occur only when the mossy fibers have reached the mature state.
Neurotrophins have also been demonstrated to offer some protection from seizure-induced injury. Tandon et al.56 blocked the synthesis of brain-derived neurotrophic factor (BDNF) by the infusion of an 18-mer antisense oligodeoxynucleotide to BDNF in the right ventricle of immature (P19) rats using micro-osmotic pumps and then subjected the rats to status epilepticus. Rats in whom BDNF synthesis was blocked experienced more cell loss in the hippocampus after status epilepticus than did control rats that did not receive oligodeoxynucleotide. These results suggest that BDNF is involved in providing protection against seizure-induced neuronal loss in the developing brain.
Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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