The neonatal period eclipses all other epochs of the human life span for the highest incidence of seizures. Neonatal seizures are associated with a high likelihood of adverse neurological outcomes including mental retardation, behavioral disorders, and epilepsy. However, it remains unclear how much of the seizure- related damage is secondary to the etiology of the seizures or the seizures per se. In the prior funding period (2002-2006) we defined the critical role of GABA in seizure genesis in neonates, demonstrating that in the developing hippocampus the GABA effect is complex, showing both excitatory and inhibitory properties. Neonatal seizures were also found to result in long-standing cognitive impairment. While this work showed the hippocampus has an important role in seizure genesis and seizure-related impairment, clinical studies have shown that most children with severe epilepsy have neocortical epilepsy. Remarkably little is known about whether GABA also has a dual role in the developing neocortex, and if so, how this affects normal brain development and seizure susceptibility. The long-term effect of neonatal seizures on neocortical function is also not known. The overall goal of the study is to better understand the role of GABA signaling in normal and abnormal brain development, starting at the cellular level and progressing into behavioral studies. This continuation proposal will revolve around the role of GABA signaling in the neocortex in normal early development as well as during seizures The first specific aim is to study developmental changes in GABA signaling in the rat neocortex. In this aim we will determine the actual developmental changes in GABA signaling in the neocortex during development including the changes in GABA(A) reversal potential (EGABA), GABA(A) driving force (DFGABA, that is the difference between EGABA and membrane potential (Em), action potential threshold, and the excitatory-to-inhibitory switch in the action of GABA.
Specific aim two will study the role of depolarizing GABA in the generation of physiological and paroxysmal activities in the immature neocortex. We will take advantage of novel recording techniques developed during the prior funding period to examine GABAergic induced plasticity in the developing neocortex. The third specific aim will evaluate the consequences of neonatal seizures on neocortical function using a combination of powerful behavioral and in vivo electrophysiological techniques. Specifically, we will assess the long-term effect of recurrent neonatal seizures on neocortical synaptic transmission and prefrontal cortex function.

Public Health Relevance

This study should provide valuable insights into the mechanisms by which seizures occur in the developing brain and the consequences of such seizures on brain development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Fureman, Brandy E
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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Hernan, A E; Holmes, G L; Isaev, D et al. (2013) Altered short-term plasticity in the prefrontal cortex after early life seizures. Neurobiol Dis 50:120-6
Isaev, Dmytro; Ivanchick, Gleb; Khmyz, Volodymyr et al. (2012) Surface charge impact in low-magnesium model of seizure in rat hippocampus. J Neurophysiol 107:417-23
Holmes, Gregory L; Bender, Alex C; Wu, Edie X et al. (2012) Maturation of EEG oscillations in children with sodium channel mutations. Brain Dev 34:469-77
Isaeva, Elena; Hernan, Amanda; Isaev, Dmytro et al. (2012) Thrombin facilitates seizures through activation of persistent sodium current. Ann Neurol 72:192-8
Isaev, Dmytro; Zhao, Qian; Kleen, Jonathan K et al. (2011) Neuroaminidase reduces interictal spikes in a rat temporal lobe epilepsy model. Epilepsia 52:e12-5
Scott, Rod C; Richard, Gregory R; Holmes, Gregory L et al. (2011) Maturational dynamics of hippocampal place cells in immature rats. Hippocampus 21:347-53
Isaeva, Elena; Isaev, Dmytro; Savrasova, Alina et al. (2010) Recurrent neonatal seizures result in long-term increases in neuronal network excitability in the rat neocortex. Eur J Neurosci 31:1446-55
Holmes, Gregory L (2009) The 2008 Judith Hoyer lecture: epilepsy in children: listening to mothers. Epilepsy Behav 16:193-202
Isaeva, Elena; Isaev, Dmytro; Khazipov, Rustem et al. (2009) Long-term suppression of GABAergic activity by neonatal seizures in rat somatosensory cortex. Epilepsy Res 87:286-9
Schmidt, Dieter; Holmes, Gregory L (2009) Commentary: novel delivery approaches for antiepileptic drugs: hope and hurdles. Neurotherapeutics 6:381-2

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