The effects of early-life seizures on the developing nervous system remain controversial. Clinical indications are that severe and repeated seizures may contribute to chronic epilepsy and impairment of learning in children. However, few experimental studies have explored this possibility. Recent studies obtained in rats suggest this may be the case since tetanus toxin-induced seizures in infancy lead of chronic focal epilepsy in hippocampus and impairment in the acquisition of spatial memory. In other experiments, recordings in adulthood from in vitro slices demonstrate abnormal epileptiform discharges arising from hippocampal area CA/3C. Morphological studies show a dramatic loss of dendritic spines on CA/3C pyramidal cells in these same chronically epileptic rats. Surprisingly the alterations seen in adulthood are not present in early- life when recurrent seizures are so frequent. These and a number of other observations lead us to propose a """"""""two hit"""""""" model of epileptogenesis. During Stage 1 of this hypothetical scheme, the developing dendrites of hippocampal pyramidal cells likely undergo a transient but significant excitotoxic insult. Thereafter, the dendrites recover, but during stage 2 high frequency interictal discharging of hippocampal networks produces a progressive epileptogenesis in which epileptic foci are strengthened and dendritic spines gradually decrease in density. In proposed electrophysiological experiments, we will systematically examine the ontogeny of the focal epilepsy in an attempt to support this hypothetical scheme. At the same time, anatomical studies will describe the development of dendritic abnormalities. Other experiments will examine how seizures produced these effects. During early postnatal life, patterns of connectivity in the central nervous system are anatomically remodeled. Widespread projections are pruned and adult patterns of connectivity result form an elaboration of synapses at selected target sites. This process of remodeling is known to rely on action potential based neuronal activity. Thus, it seems plausible that the abnormal activity that accompanies frequent seizures may activate remodeling mechanisms to produced abnormal patterns of connectivity. Since seizures in area CA3 are mediated by recurrent excitatory synapses, they likely undergo long term potentiation (LTP). However, afferents projects to these cells but not participating in seizures may undergo heterosynaptic long term depression (LTD). Experiments in in vitro slices support this notion. Thus, LTP of recurrent excitation could lead to persistent epileptiform activity while heterosynaptic LTD may lead to synapse loss. Dendritic spine loss could be a consequence of a partial deafferentation of pyramidal cell dendrites. Preliminary results appear to support this idea since the highly specialized dendritic spines and presynaptic terminals of the mossy fiber pathway are both reduced in number in epileptic rats. Proposed studies will verify these anatomical alterations and examine their physiological impact. Other experiments will attempt to prevent the development of epilepsy by chronically treating rats with NMDA receptor antagonists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037171-03
Application #
6330526
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-01-15
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$221,676
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Lee, Chong L; Frost Jr, James D; Swann, John W et al. (2008) A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia 49:298-307
Swann, John W; Le, John T; Lam, Trang T et al. (2007) The impact of chronic network hyperexcitability on developing glutamatergic synapses. Eur J Neurosci 26:975-91
Swann, John W; Le, John T; Lee, Chong L (2007) Recurrent seizures and the molecular maturation of hippocampal and neocortical glutamatergic synapses. Dev Neurosci 29:168-78
Jiang, M; Swann, J W (2005) A role for L-type calcium channels in the maturation of parvalbumin-containing hippocampal interneurons. Neuroscience 135:839-50
Galvan, Cynthia D; Wenzel, Jurgen H; Dineley, Kelly T et al. (2003) Postsynaptic contributions to hippocampal network hyperexcitability induced by chronic activity blockade in vivo. Eur J Neurosci 18:1861-72
Oliva Jr, Anthony A; Lam, Trang T; Swann, John W (2002) Distally directed dendrotoxicity induced by kainic Acid in hippocampal interneurons of green fluorescent protein-expressing transgenic mice. J Neurosci 22:8052-62
Lee, C L; Hannay, J; Hrachovy, R et al. (2001) Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy. Neuroscience 107:71-84
Swann, J W; Smith, K L; Lee, C L (2001) Neuronal activity and the establishment of normal and epileptic circuits during brain development. Int Rev Neurobiol 45:89-118
Jiang, M; Oliva Jr, A A; Lam, T et al. (2001) GABAergic neurons that pioneer hippocampal area CA1 of the mouse: morphologic features and multiple fates. J Comp Neurol 439:176-92

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