The highest incidence of seizures across the lifespan occurs in the neonatal period, and seizures in early life are associated with later life epilepsy, and significant neurocognitive and behavioral deficits. Our prior studies have shown that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPAR) subtype of the excitatory glutamate receptor is highly expressed in the rodent and human brain throughout the neonatal period, and is a critical mediator of the later epilepsy and behavioral comorbidities. The present proposal extends these studies and provides better preclinical assay systems for analysis of epileptogenesis and neurobehavior in both the rat and mouse model (Aim 1).
We aim to better understand the mechanisms of seizure-induced alterations in network plasticity in order to identify reversible changes (Aim 2). Thus, we will extend our studies on the consequences of seizure-induced modifications of mammalian target of rapamycin (TOR) and Fragile X mental retardation protein (FMRP) pathways, and investigate the extent that brief pharmacologic manipulation of these pathways will decrease later life epilepsy and neurobehavioral deficits (Aim 3). Finally, we will study human tissue to determine whether there is evidence of dysregulation of AMPARs, mTOR or FMRP pathways in human brain tissue from neonates and infants with epilepsy (Aim 4). The overall goal of this ongoing research program is to identify mechanisms whereby this common form of seizures may induce later life epilepsy, cognitive and neurobehavioral deficits, including autism. The emphasis is on identifying therapeutic targets, preclinical disease modifying trials with clinically relevant outcomes, and validating these targets in human tissue to pave the way for translation clinical investigation.

Public Health Relevance

The recent Institute of Medicine Report on Epilepsy estimates that 1 in 26 Americans will develop epilepsy over their lifetime, and early life/infancy and the elderly account for the highest burden. The present proposal focuses on neonatal seizures, which are the most common form of early life epilepsy, with an incidence of 1.5- 3 per thousand live births. These seizures are poorly responsive to conventional antiepileptic drugs (AEDs), and this is thought to be due to unique attributes of the infant brain. There exists no FDA- approved drug that is fully effective in neonatal seizures, and to date there is no approved cure or disease modifying treatment for epileptogenesis in the developing or adult brain. Neonatal seizures and early life epilepsy can result in long term epilepsy, as well as later life cognitive and behaviora deficits including autism. The most common source of neonatal seizures is perinatal hypoxic/ischemic encephalopathy (HIE), and the present proposal uses our rodent model established over the 20 years of this research program that recapitulates some of the human features of drug resistance, epileptogenesis, and cognitive/behavioral deficits. We would like to emphasize that work done on this project has provided the basis for the only TWO human neonatal seizure trials for bumetanide and levetiracetam ( NCT00830531;NCT00720863) as well as a trial to modify the drug topiramate to a parenteral form for human use in neonatal seizures (NCT00753493). Furthermore, this grant has led to some of the only published ant epileptogenic disease- modifying treatments for neonatal seizures, using clinically available drugs. This grant application addresses several components of the Epilepsy Research Benchmarks ( Area I. Prevent epilepsy and its progression D. Identify new ways to prevent epilepsy or stop it once it begins E. Develop new animal models to study epileptogenesis. Area II. Develop new treatment strategies and improve current approaches in order to cure epilepsy C. Improve current treatments and develop new technologies Area III: Prevent, limit, and reverse the co-morbidities associated with epilepsy and its treatment. B. Identify predictors and underlying mechanisms that contribute to co-morbidities. C. Determine the optimal treatments for the neuropsychiatric and cognitive co- morbidities in people with epilepsy. D. Prevent or limit other adverse consequences occurring in people with epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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University of Pennsylvania
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Sun, Hongyu; Juul, Halvor M; Jensen, Frances E (2016) Models of hypoxia and ischemia-induced seizures. J Neurosci Methods 260:252-60
Lippman-Bell, Jocelyn J; Zhou, Chengwen; Sun, Hongyu et al. (2016) Early-life seizures alter synaptic calcium-permeable AMPA receptor function and plasticity. Mol Cell Neurosci 76:11-20
Jantzie, Lauren L; Talos, Delia M; Jackson, Michele C et al. (2015) Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. Cereb Cortex 25:482-95
Jantzie, Lauren L; Hu, Melody Y; Park, Hyun-Kyung et al. (2015) Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia. Pediatr Res 77:554-62
Simonato, Michele; Brooks-Kayal, Amy R; Engel Jr, Jerome et al. (2014) The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol 13:949-60
Loddenkemper, Tobias; Talos, Delia M; Cleary, Ryan T et al. (2014) Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus. Epilepsy Res 108:605-15
Cleary, Ryan T; Sun, Hongyu; Huynh, Thanhthao et al. (2013) Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures. PLoS One 8:e57148
Talos, Delia M; Chang, Meayoung; Kosaras, Bela et al. (2013) Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res 73:24-30
Lippman-Bell, Jocelyn J; Rakhade, Sanjay N; Klein, Peter M et al. (2013) AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures. Epilepsia 54:1922-32
Sun, Hongyu; Kosaras, Bela; Klein, Peter M et al. (2013) Mammalian target of rapamycin complex 1 activation negatively regulates Polo-like kinase 2-mediated homeostatic compensation following neonatal seizures. Proc Natl Acad Sci U S A 110:5199-204

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