The long term objectives of this project are to understand the relationship between seizures and brain development. As shown in the progress report, we have recently discovered an exception to the general rule that the immature brain is selectively resistant to seizure-induced damage. The goals for the upcoming period of this project will be to explore the limits and significance of that exception. This will be done in four general areas: (A) seizure induced neuronal injury, ( of inhibition in the dentate gyrus, CC) epileptogenicity, (D) induction of sprouting. A. We will establish by quantitative histological methods whether sustained perforant path stimulation induces irreversible neuronal loss in 15 day old rats, and will compare the distribution and time course of damage to that observed in the adult after similar stimulation. We expect that similar durations of stimulation will induce less severe legions at younger ages, and that this resistance will not be absolute. We will define by immunocytochemistry and in situ hybridization the subpopulations of hila neurons which sustain damage, and expect a different distribution as a function of age. We will treat the animals with blockers of NMDA and non NMDA glutamate receptors.a We expect to protect selective subpopulations with those agents. We will test the effect of SE on the immature brain in the rabbit, a species which is very immature at birth, the guinea pig, which is very mature at birth; and the marmoset which is intermediate. B. We will study the effect of sustained perforant path stimulation on paired pulse inhibition in the dentate gyrus. We will follow the time course of this loss of inhibition during the recovery period and the period of sprouting. C. We will study the epileptogenicity of lesions. We expect that spontaneous seizures and accelerated kindling will be observed in animals following perforant path stimulation of sufficient severity to induce neuronal loss. 0. We will study sprouting by Timm stain, and by immunocytochemistry and in situ hybridization studies of GAP 43, NAP2, and GFAP. We will also study the induction of neurotrophins and of their receptors. These studies will define the risk of hippocampal damage from epileptic seizures during early childhood in several species, and should help clinicians to understand the basic principles that underlay treatment of non convulsive seizures.
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