One of the most frequent and important questions asked by parents of children with epilepsy is whether seizures can lead to brain damage. This is a difficult clinical problem to study since cognitive impairment and behavioral abnormalities may be related to the etiological agent responsible for the seizures, age at time of onset of seizures, the type, frequency, or duration of the seizures, or the antiepileptic drugs used to treat the seizures. Many of these variables can be eliminated by using animal models of epilepsy. Work in our laboratory using the kainic acid (KA) model has demonstrated that status epilepticus in prepubescent and mature rats leads to significant deficits in memory, learning and behavior as adults when compared to control littermates without seizures. These rats also had a high incidence of spontaneous recurrent seizures (SRS) and an increased susceptibility to seizures using kindling and flurothyl. However, younger animals (<20 day old) with KA-induced seizures of similar severity were not associated with later neurological deficits. The immature animals also had a low rate of SRS and did not differ from controls in susceptibility to kindling or flurothyl. In preliminary results, we have also found that continuous hippocampal stimulation (CHS) in the mature rat brain, but not immature rats, leads to deficits in memory and activity level. Pathophysiological mechanisms that """"""""protect"""""""" the young brain from long-term detrimental effects of prolonged seizures are unknown. Since the observation that prolonged seizures in the immature brain have no-long term consequences may have substantial clinical consequences, we wish to expand these preliminary observations. To verify that age at the time of KA administration is a critical factor in the later development of neurological deficits we will subject KA-treated rats to a variety of behavioral tests at a fixed interval, as opposed to a fixed age, following the KA. The role of spontaneous recurrent seizures on subsequent learning, memory, behavior, and seizure susceptibility will be studied by correlating seizure frequency, using continuous video monitoring, with behavioral testing. To determine if the age-dependent changes are due to a greater recovery or plasticity in the immature brain, we will perform serial behavioral and histological examinations following administration of KA. To determine if the immature brain is """"""""more resistant"""""""" to excitatory amino acids presumably released during seizures we will assess the behavioral and histological sequelae following intracerebroventricular administration of glutamate and aspartate. In parallel studies, both competitive and noncompetitive intracerebroventricular NMDA antagonists will be given following KA to determine whether damage which occurs following KA can be altered. Finally, to determine whether our findings that long-term sequelae following prolonged seizures is an age-dependent phenomenon is applicable to other models, we will expand our preliminary studies with CHS. Inferences reached in this study should increase our understanding of the importance of age of onset and the mechanisms for such age-specific differences in neurological sequelae following seizures.
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| Holmes, Gregory L; Zhao, Qian (2008) Choosing the correct antiepileptic drugs: from animal studies to the clinic. Pediatr Neurol 38:151-62 |
| Zhou, Jun-Li; Shatskikh, Tatiana N; Liu, Xianzeng et al. (2007) Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 25:3667-77 |
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| Zhou, Jun-Li; Zhao, Qian; Holmes, Gregory L (2007) Effect of levetiracetam on visual-spatial memory following status epilepticus. Epilepsy Res 73:65-74 |
| Zhou, Jun-Li; Lenck-Santini, Pierre-Pascal; Holmes, Gregory L (2007) Postictal single-cell firing patterns in the hippocampus. Epilepsia 48:713-9 |
| Shatskikh, Tatiana N; Raghavendra, Meghana; Zhao, Qian et al. (2006) Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats. Epilepsy Behav 9:549-56 |
| Holmes, Gregory L; Lenck-Santini, Pierre-Pascal (2006) Role of interictal epileptiform abnormalities in cognitive impairment. Epilepsy Behav 8:504-15 |
| Zhao, Qian; Marolewski, Ariane; Rusche, James R et al. (2006) Effects of uridine in models of epileptogenesis and seizures. Epilepsy Res 70:73-82 |
| Lai, Ming-Chi; Holmes, Gregory L; Lee, Ko-Hung et al. (2006) Effect of neonatal isolation on outcome following neonatal seizures in rats--the role of corticosterone. Epilepsy Res 68:123-36 |
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