Temporal lobe epilepsy is a serious disease for which there is no preventative and no cure. Moreover, available therapies are often ineffective, and medication side effects can be severe, particularly in children. In an effort to develop better treatments for the disease, we seek to understand how normal brains become epileptic. Elucidating the mechanisms of epileptogenesis will prove critical for treating, and ultimately curing, the disease. Recent advances in neuroscience have revealed that new brain cells are generated in adults. While these new brain cells likely play important roles in healthy humans, we believe that abnormal development and integration of these new cells contributes to the development of epilepsy. To determine whether adult-generated brain cells should be targeted for developing new treatments for epilepsy, we have developed a mouse model system which allows us to compare the structure of existing and newly-generated brain cells during the development of epilepsy. These studies will establish whether the new cells are selectively vulnerable to developing changes likely to promote epilepsy. Initial studies confirm the newborn cells develop hallmark pathologies of the epileptic brain, while mature cells appear unaffected. In a second set of experiments, we will examine the impact of seizures on the integration of new brain cells. Epilepsy frequently develops following neurological injuries such as head trauma, hypoxia or status epilepticus. Abnormal integration of new brain cells may result as a direct consequence of this initial injury. Alternatively, the initial injury may result in the occurrence of spontaneous seizures, and these seizures, in turn, may disrupt new cell integration. To distinguish between these possibilities, seizure frequency will be assessed in mice for several months following an epileptogenic brain insult. The morphology of cells born after the insult will be correlated with the presence and frequency of seizures in these animals. Importantly, the outcome of this study will determine whether seizure control might be an effective target for promoting the correct integration of newborn brain cells. Finally, to determine whether abnormally integrated newborn brain cells can be targeted to cure epilepsy, we will utilize a transgenic mouse model which will allow us to selective ablate newborn cells from the epileptic brain. These studies will be the first to examine the impact of selectively ablating any abnormal cell population from the epileptic brain, and it is our hope that our findings will provide the basis for developing new and more effective treatments for epilepsy.

Public Health Relevance

In adults, new brain cells are born daily in the hippocampus, a region pivotal to the development of common forms of epilepsy. Abnormal incorporation of these new cells into the brain may promote the development of the disease. This proposal will elucidate the contribution of these new neurons to pathology, development and maintenance of epilepsy. By determining how normal brains become epileptic, we can begin to develop therapies to delay, halt and ultimately reverse the process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062806-04
Application #
8282926
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2009-08-05
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$321,563
Indirect Cost
$107,188
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Hester, Michael S; Danzer, Steve C (2014) Hippocampal granule cell pathology in epilepsy - a possible structural basis for comorbidities of epilepsy? Epilepsy Behav 38:105-16
Hester, Michael S; Danzer, Steve C (2013) Accumulation of abnormal adult-generated hippocampal granule cells predicts seizure frequency and severity. J Neurosci 33:8926-36
Hofacer, Rylon D; Deng, Meng; Ward, Christopher G et al. (2013) Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol 73:695-704
Singh, Shatrunjai P; He, Xiaoping; McNamara, James O et al. (2013) Morphological changes among hippocampal dentate granule cells exposed to early kindling-epileptogenesis. Hippocampus 23:1309-20
Murphy, Brian L; Hofacer, Rylon D; Faulkner, Christian N et al. (2012) Abnormalities of granule cell dendritic structure are a prominent feature of the intrahippocampal kainic acid model of epilepsy despite reduced postinjury neurogenesis. Epilepsia 53:908-21
Danzer, Steve C (2012) Depression, stress, epilepsy and adult neurogenesis. Exp Neurol 233:22-32
Murphy, Brian L; Danzer, Steve C (2011) Somatic translocation: a novel mechanism of granule cell dendritic dysmorphogenesis and dispersion. J Neurosci 31:2959-64
McAuliffe, John J; Bronson, Stefanie L; Hester, Michael S et al. (2011) Altered patterning of dentate granule cell mossy fiber inputs onto CA3 pyramidal cells in limbic epilepsy. Hippocampus 21:93-107
Santos, V R; de Castro, O W; Pun, R Y K et al. (2011) Contributions of mature granule cells to structural plasticity in temporal lobe epilepsy. Neuroscience 197:348-57
Murphy, Brian L; Pun, Raymund Y K; Yin, Hulian et al. (2011) Heterogeneous integration of adult-generated granule cells into the epileptic brain. J Neurosci 31:105-17