The studies proposed in this application are based on the premise that seizures in early-life contribute to the intellectual disabilities that are commony associated with childhood epilepsy. Recent clinical investigations support the idea that the cognitive comorbidities of epilepsy have a neurodevelopmental origin and that epilepsy interferes in some way with normal brain growth and maturation. Experiments in animal models support this hypothesis. For instance, we have shown that brief but recurring seizures in infant mice or rats lead to long term deficits in spatial learning and memory. While these early-life seizures do not kill neurons, the dendrites of hippocampal pyramidal cells show significant anatomical alterations. Among them are reductions in spine density, dendrite branch number and length. In exploring the mechanism for these dendritic abnormalities, results from experiments during the last funding cycle showed that repetitive infantile seizures suppress the growth of CA1 hippocampal pyramidal cell dendrites. Nearly identical results have been obtained in a hippocampal slice culture model where persistent electrographic activity also blocked dendrite growth. In these experiments, we also found that signaling to the transcription factor CREB was reduced in CA1 pyramidal cells. Since CREB is an important regulator of activity-dependent dendrite growth, we have undertaken additional experiments to understand its potential role in seizure-induced dendrite growth suppression. Results indicate that electrographic seizure activity """"""""shuts-off"""""""" signaling to both CREB and its co- activator CRTC1. Moreover, signaling of the neurotrophin NT4 to CREB and CRTC1 is also blocked by seizure activity. This leads us to hypothesize that seizures suppress the dendrite growth promoting properties of the neurotrophins, which contributes to aberrant growth in epilepsy. Experiments are proposed to further characterize the impact seizures have on the actions of neurotrophin. In slice culture, biochemical experiments will characterize the alterations in neurotrophin signaling through the Ras-MAPK, PI3K-AKT and PLCy- IP3/DAG pathways. We will also attempt to protect against seizure-induced suppression of neurotrophin signaling by suppressing calcium entry into cells with NMDA receptor antagonists and overexpression of the K+ channel, Kir2.1. Live 2-photon time-lapse imaging both in vivo and in vitro will study the dynamics of dendrite growth after periods of seizure activity. We will also examine dendritic responses to the neurotrophins. Other in vivo experiments will attempt to show that the abnormalities in neurotrophin signaling found in vitro occur after recurrent seizures in infant mice. We will use the TrkB agonist, 7, 8-dihydroxyflavone to assay alterations in neurotrophin signaling. In addition, we will attempt to show that the dendrite growth induced by 7, 8-dihydroxyflavone is suppressed by prior seizures. Identifying the mechanisms of seizure-induced dendrite growth suppression should lead to a much better understanding of seizure-induced cognitive disabilities and ways to prevent them.

Public Health Relevance

Experiments proposed in this application are aimed at furthering an understanding of the biological origins of intellectual disabilities that are commonl observed in children with intractable epilepsy. Our research has shown that recurring seizures suppress the normal growth of nerve cell dendrites and may suppress the actions of growth factors that stimulate dendrite growth. Experiments are planned to investigate how the actions of growth factors are blocked so that ways can be developed to permit normal growth and prevent seizure-induced intellectual disabilities.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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Baylor College of Medicine
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Nishimura, Masataka; Casanova, J R; Swann, John W (2017) The Impact of Electrographic Seizures on Developing Hippocampal Dendrites Is Calcineurin Dependent. eNeuro 4:
Frost Jr, James D; Le, John T; Lee, Chong L et al. (2015) Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis 82:1-11
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

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