In some children epilepsy can be catastrophic, leading to mental retardation and behavioral and psychiatric disturbances. While the etiology of the seizures or antiepileptic drugs may contribute to these problems, there is increasing evidence that recurrent seizures during development can be detrimental. In preliminary studies we have demonstrated that neonatal seizures are associated with cognitive disturbances and a reduced seizure threshold when animals are tested as adults. In addition, recurrent seizures are associated with increased neurogenesis and cell number in the dentate gyrus and sprouting in the dentate supragranular region and CA3. Rather than producing cell loss, we propose that in the immature brain seizure-related brain injury is caused by the development of aberrant and maladaptive neuronal circuits. All of the specific aims revolve around this central hypothesis which will be addressed by using neuropathologic, physiologic, and behavioral approaches in two laboratories, the Developmental Neurophysiology Laboratory at Children's Hospital in Boston and the Laboratoire de Epilepsie at Ischemie Cerebrale, under the direction of Dr. Ben-Ari, in Paris. In the first specific aim we will characterize the time course of seizure-induced increases in neurogenesis of dentate granule cells to determine the relationship between seizure number and neurogenesis and the duration of the increased neurogenesis following seizures. To determine if an over-production of dentate granule cells is responsible for the observed sprouting, we will compare the ratio of dentate granule cells to CA3 neurons with quantified measures of sprouting. In the second specific aim we will address the question of whether newly formed granule cells are the cells of origin for the aberrant sprouting in the CA3 and supragranular region.
This aim will be achieved by labeling granule cells using 5'-bromodeoxyuridine and Fleuro-Red from rats subjected to neonatal seizures. We will also measure sprouting following a series of neonatal seizures in which neurogenesis is suppressed by irradiation. To learn whether recurrent seizures are associated with any compensatory cell loss, in the third specific aim we will measure necrosis and apoptosis at various times after the seizures. The electrophysiological consequences of recurrent seizures during early development will be assessed in the fourth specific aim. Hippocampal slices from mature rats subjected to neonatal seizures will be evaluated for changes in excitatory/inhibitory neurotransmission. The functional consequences of these seizure-induced changes in synaptic organization will be studied in the fifth specific aim when we will perform correlations between sprouting and learning in spatial and auditory tasks. Using the expertise of two laboratories it is anticipated that this proposal will provide insights into the mechanism by which recurrent seizures lead to brain damage in young children.
| Khan, Omar I; Zhao, Qian; Miller, Forrest et al. (2010) Interictal spikes in developing rats cause long-standing cognitive deficits. Neurobiol Dis 39:362-71 |
| 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 |
| Zhou, Jun-Li; Lenck-Santini, Pierre-Pascal; Zhao, Qian et al. (2007) Effect of interictal spikes on single-cell firing patterns in the hippocampus. Epilepsia 48:720-31 |
| 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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