The studies proposed in this application are based on the premise that recurring seizures in early-life contribute to cognitive deficits in children with intractable epilepsy. Animal models of early-onset epilepsy have advanced our understanding of the effects seizures have on brain development. Several laboratories have shown that infantile recurring seizures can produce deficits in learning and memory. These effects are not explained by the death of neurons. However, dendritic abnormalities in hippocampal pyramidal cells - including a reduction in dendritic branching - have been reported. Consistent with this observation are recent findings of decreased expression of dendritic glutamatergic postsynaptic proteins. In the progress report, we show that these effects are reproduced in an in vitro model of developmental epilepsy, where epileptiform activity is induced in hippocampal slice cultures by treatment with a GABAa receptor antagonist. During the course of these studies evidence began to accumulate that the primary deficit produced by epileptiform activity was not on glutamatergic synaptic transmission but on dendrites. Further studies confirmed this and showed that chronic disinhibition actually prevents the growth of dendrites and in a NMDA receptor dependent manner. Using our in vitro model, additional studies explored molecular mechanisms responsible for the suppression of dendrite growth. Results showed that activity through a signaling cascade previously implicated in dendrogenesis, the MAPK-CREB signaling pathway, is """"""""shut-off"""""""" by chronic network hyperexcitability. Our most recent results have confirmed 3 critical aspects of our in vitro data in an in vivo model. Based on these results we hypothesize that recurrent seizures in early-life suppress the growth of dendrites and the """"""""shut-off"""""""" in signaling to CREB contributes to dendrite growth suppression. To test these hypotheses four specific aims are proposed. Using the Flurothyl Model we plan to directly demonstrate that recurrent seizures suppress the growth of dendrites. Dendrite reconstructions at selected developmental time points will attempt to show that developmental increases in animals that have experienced seizures lag behind those observed in controls. The functional consequences of growth suppression will be examined electrophysiologically. Other experiments will assess the NMDA receptor dependency of dendrite growth suppression as well as seizure-induced learning deficits. Additional studies in vivo will set out to show that the shut-off in CREB signaling is an antecedent of and therefore potentially causative in growth suppression. Transfections of slice culture neurons with the constitutively active form of CREB are aimed at directly implicating a shut-off in CREB signaling in dendrite growth suppression. By identifying the cellular and molecular events responsible for dendrite growth suppression, novel therapies may be developed to prevent learning deficits produced by recurring seizures.
Children with severe epilepsy are often learning impaired. Similar observations have been made in young animals that have experienced seizures. Results suggest that developing neurons grow abnormally slow after seizures. We are studying why this happens so therapies can be developed to prevent learning disabilities.
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|Casanova, J R; Nishimura, Masataka; Swann, John W (2014) The effects of early-life seizures on hippocampal dendrite development and later-life learning and memory. Brain Res Bull 103:39-48|
|Lugo, Joaquin N; Swann, John W; Anderson, Anne E (2014) Early-life seizures result in deficits in social behavior and learning. Exp Neurol 256:74-80|
|Weston, Matthew C; Chen, Hongmei; Swann, John W (2014) Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures. Front Mol Neurosci 7:1|
|Casanova, J R; Nishimura, M; Le, J et al. (2013) Rapid hippocampal network adaptation to recurring synchronous activity--a role for calcineurin. Eur J Neurosci 38:3115-27|
|Weston, Matthew C; Chen, Hongmei; Swann, John W (2012) Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci 32:11441-52|
|Frost Jr, James D; Lee, Chong L; Le, John T et al. (2012) Interictal high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis 46:377-88|
|Nishimura, Masataka; Gu, Xue; Swann, John W (2011) Seizures in early life suppress hippocampal dendrite growth while impairing spatial learning. Neurobiol Dis 44:205-14|
|Frost Jr, James D; Lee, Chong L; Hrachovy, Richard A et al. (2011) High frequency EEG activity associated with ictal events in an animal model of infantile spasms. Epilepsia 52:53-62|
|Nishimura, Masataka; Owens, James; Swann, John W (2008) Effects of chronic network hyperexcitability on the growth of hippocampal dendrites. Neurobiol Dis 29:267-77|
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