Brain injury induces the subsequent development of epilepsy by unknown mechanisms. The primary unmet need and most urgent issue to address in epilepsy research is characterization of the biological factors underlying this process, which has been termed epileptogenesis. This is the focus of the present application. We have preliminary data implicating injury-mediated upregulation of a transcriptional repressor, Repressor Element 1 silencing transcription factor (REST) as a significant contributor to epilepsy disease development. REST is induced transiently by epileptogenic injury, and represses the expression of key genes in hippocampal neurons, altering limbic synaptic and circuit function, which in turn contributes to epilepsy development. Blocking REST effects, either indirectly by targeting REST-mediated transcriptional repression, or directly by blunting REST upregulation, reverse the synaptic and circuit effects evident during epileptogenesis, and retards or stops the subsequent development of epilepsy. Based on this preliminary data, we have formulated a Central Hypothesis: Epileptogenesis is a consequence of REST-mediated epigenetic modification in expression of key genes regulating excitability of the hippocampal dentate gyrus. In the present proposal, this Central Hypothesis will be tested in a series of studies integrating state of the art dynamic imaging, patch clamp, gene targeting, and in vivo recording techniques. We propose to examine how a) selective deletion of REST in forebrain principal neurons;b) selective deletion of REST in neurons within the hippocampal dentate gyrus or area CA1;and c) selective, temporally regulated synaptic silencing of dentate granule neurons modifies or blocks epilepsy onset and hippocampal circuit perturbations, both of which develop following status epilepticus. Successful implementation of these experimental approaches should provide significant insight into the mechanisms underlying the injury/epilepsy link responsible for acquired epilepsies. Understanding the mechanisms contributing to epilepsy emergence will immediately suggest new therapies targeting epileptognesis, many of which could translate quickly to the clinic.

Public Health Relevance

Despite the fact that epilepsy is one of the most common chronic neurologic disorders, we know very little about the mechanisms which link brain injury with the subsequent emergence of spontaneous seizures, the clinical hallmark of epilepsy. This proposal will examine these mechanisms, focusing on the role of a specific repressor of gene transcription, which may play a significant role in epilepsy development. Using advanced imaging, patch clamp recording, gene targeting, and in vivo techniques in animal models of epilepsy, we will determine the mechanisms linking brain injury to epilepsy, facilitating the development of better, more effective treatments for the disease process underlying epilepsy development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS038572-11A1
Application #
8319876
Study Section
Special Emphasis Panel (ZRG1-BDCN-M (02))
Program Officer
Stewart, Randall R
Project Start
1999-05-06
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
11
Fiscal Year
2012
Total Cost
$503,398
Indirect Cost
$156,630
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Dengler, C G; Coulter, D A (2016) Normal and epilepsy-associated pathologic function of the dentate gyrus. Prog Brain Res 226:155-78
Dulla, Chris G; Coulter, Douglas A; Ziburkus, Jokubas (2016) From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease. Neuroscientist 22:295-312
Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki et al. (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:6606
Coulter, Douglas A; Steinhäuser, Christian (2015) Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med 5:a022434
Iyengar, Sloka S; LaFrancois, John J; Friedman, Daniel et al. (2015) Suppression of adult neurogenesis increases the acute effects of kainic acid. Exp Neurol 264:135-49
Jiang, Yindi; Hsieh, Jenny (2014) HDAC3 controls gap 2/mitosis progression in adult neural stem/progenitor cells by regulating CDK1 levels. Proc Natl Acad Sci U S A 111:13541-6
Kuzum, Duygu; Takano, Hajime; Shim, Euijae et al. (2014) Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging. Nat Commun 5:5259
Yu, Esther P; Dengler, Christopher G; Frausto, Shanti F et al. (2013) Protracted postnatal development of sparse, specific dentate granule cell activation in the mouse hippocampus. J Neurosci 33:2947-60
Goldberg, Ethan M; Coulter, Douglas A (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci 14:337-49
Coulter, Douglas A; Yue, Cuiyong; Ang, Chyze Whee et al. (2011) Hippocampal microcircuit dynamics probed using optical imaging approaches. J Physiol 589:1893-903

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