Elucidating the basic mechanisms by which a normal brain is transformed into an epileptic brain has been a holy grail of epilepsy research for decades. If the mechanisms of epileptogenesis can be understood, then new treatments and therapies can be designed to target these processes to prevent - and possibly cure - epilepsy. While years of research have revealed a multitude of changes that occur during epileptogenesis, one basic problem has been distinguishing changes that mediate epileptogenesis from changes that are associated with the disease, but play no causal role. This problem is evident for almost all existing models of epilepsy, which produce widespread brain damage and cellular changes, thereby making the proximal cause of the disease difficult to ascertain. For the present proposal, we make a pivotal advance by utilizing a novel mouse model of epilepsy generated in the first term of this grant, in which epilepsy develops following conditional, inducible deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from a subset (>5%) of hippocampal dentate granule cells (DGC). Excessive activation of the mTOR pathway is implicated in the development of temporal lobe epilepsy, and the effect of this deletion - to induce the abnormal integration of newborn DGC - is important because abnormal newborn DGC are a hallmark pathology of temporal lobe epilepsy, and are suspected of causing the disease. Our study provides direct evidence that abnormal DGC can cause epilepsy. Having demonstrating that abnormal DGC can be a proximal cause of epilepsy, we now seek to elucidate the mechanism(s) by which these cells promote seizures. Our guiding hypothesis is that abnormal DGCs promote epileptogenesis initially through cell-intrinsic increases in connectivity and activity, and secondarily by inducing changes among neighboring granule cells and their downstream targets. To test this hypothesis, we will determine the primary features of abnormal cells in SA1, the temporal associations between primary and secondary changes and epileptogenesis in SA2, and the functional significance of these changes in SA3 and 4.

Public Health Relevance

The present proposal utilizes a novel mouse model of epilepsy, in which the brain malformation that causes the disease can be genetically controlled by the investigator. Using this model, we will gain a unique window into the series of brain changes that lead to epilepsy, which will provide a roadmap for the development of new treatments for the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS065020-06
Application #
8697629
Study Section
Special Emphasis Panel (ZRG1-DBD-M (08))
Program Officer
Whittemore, Vicky R
Project Start
2009-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$341,250
Indirect Cost
$122,500
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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