Epilepsy is the third most common chronic neurological disorder, affecting 2.5 million persons in the USA. Temporal lobe epilepsy (TLE), with seizures involving the hippocampal circuit, is one of the most severe epilepsies in adults, and is refractory to medical treatment in >30% of individuals. TLE is commonly preceded by febrile status epilepticus (FSE). Whereas the relationship of FSE to human TLE is not fully understood, experimental FSE provokes TLE in animal models, suggesting that FSE might contribute to epileptogenesis in both normal and predisposed brain. Importantly, the contribution of FSE to TLE (as a 1st or 2nd hit) may be predictable and preventable. TLE commonly affects the young, exacting a tremendous toll on human potential. However, there are major challenges in preventing or aborting TLE: (1) We do not know the mechanisms for the contribution of FSE to TLE;(2) We do not have predictive markers to identify the 30-40% of those experiencing FSE who will proceed to develop TLE;(3) We do not have mechanism-based drugs to abort the epileptogenic process that bridges FSE and TLE. The three specific aims of this competing renewal proposal address these major challenges. We capitalize on results obtained during the current award period, on our published and novel findings regarding the molecular, cellular and network changes that follow FSE and contribute to epileptogenesis, and on exciting data supporting clinically-translatable predictive markers. We employ innovative methods in in vitro and in vivo systems, and integrate hypothesis-driven and large scale gene expression analyses. We devise innovative decoy and mimic approaches for both probing mechanistic questions and for potential translation. Our work to date has revolutionized the scientific approach to the study of febrile seizures and their consequences, has been published in high-impact journals and has been cited >4000 times. In this renewal application, we embark on highly novel, bench-derived yet translatable solutions to a major human health problem.

Public Health Relevance

Epilepsy is the third most common chronic neurological disorder, affecting 2.5 million persons in the USA. Temporal lobe epilepsy (TLE) is one of the most severe and difficult to treat epilepsies. This epilepsy is commonly preceded by febrile status epilepticus (FSE), and while the relationship of FSE to human TLE is not fully understood, in animal models, experimental FSE provokes TLE, suggesting that FSE might contribute to TLE in people. Importantly, the contribution of FSE to TLE (as a 1st or 2nd hit) may be predictable and preventable. TLE commonly affects the young, exacting a tremendous toll on human potential. Here we build on important information to answer three crucial questions (1) how does experimental FSE provoke TLE? (2) Can we predict early the 30-40% of individuals with FSE who will eventually develop TLE? (3) Can we use experimental drugs arising from our studies to abort epilepsy in individuals predicted to develop the disorder? Obviously, the ability to prevent epilepsy in children at high risk will make a huge difference.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS035439-16
Application #
8810580
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
Patterson, Katelin P; Baram, Tallie Z; Shinnar, Shlomo (2014) Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus. Neurotherapeutics 11:242-50
Choy, ManKin; Dubé, Celine M; Patterson, Katelin et al. (2014) A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J Neurosci 34:8672-84
Surges, Rainer; Kukley, Maria; Brewster, Amy et al. (2012) Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy. Biochem Biophys Res Commun 420:156-60
Han, Ye; Noam, Yoav; Lewis, Alan S et al. (2011) Trafficking and gating of hyperpolarization-activated cyclic nucleotide-gated channels are regulated by interaction with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) and cyclic AMP at distinct sites. J Biol Chem 286:20823-34
Hill, Elisa L; Hosie, Suzanne; Mulligan, Rachel S et al. (2011) Temperature elevation increases GABA(A) -mediated cortical inhibition in a mouse model of genetic epilepsy. Epilepsia 52:179-84
Kanyshkova, Tatyana; Pawlowski, Matthias; Meuth, Patrick et al. (2009) Postnatal expression pattern of HCN channel isoforms in thalamic neurons: relationship to maturation of thalamocortical oscillations. J Neurosci 29:8847-57
Dube, Celine M; Brewster, Amy L; Richichi, Cristina et al. (2007) Fever, febrile seizures and epilepsy. Trends Neurosci 30:490-6
Dube, Celine (2007) Neuropeptide Y: potential role in recurrent developmental seizures. Peptides 28:441-6
Bender, Roland A; Kirschstein, Timo; Kretz, Oliver et al. (2007) Localization of HCN1 channels to presynaptic compartments: novel plasticity that may contribute to hippocampal maturation. J Neurosci 27:4697-706
Brewster, Amy L; Chen, Yuncai; Bender, Roland A et al. (2007) Quantitative analysis and subcellular distribution of mRNA and protein expression of the hyperpolarization-activated cyclic nucleotide-gated channels throughout development in rat hippocampus. Cereb Cortex 17:702-12

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