Epilepsies are often associated with abnormalities in brain structure. These abnormalities take many different forms, and can be a consequence of gene mutations, perinatal insults, or brain trauma. The aberrant structures collectively sometimes referred to as cortical dysplasias frequently reflect developmental brain defects. We propose to study an animal model of one type of cortical dysplasia, called periventricular nodular heterotopia (PNH). This condition is most frequently a result of a gene mutation that interferes with normal migration of newborn cells into their proper location in the cortex. Most people with this condition suffer from a seizure disorder, often unresponsive to medication. Some clinical studies have suggested these heterotopias serve as initiation sites of epileptic discharge and/or seizures, but these studies have been unable to establish an unequivocal cause-effect relationship between structural and functional abnormalities. Our goal in the current proposal is to gain insight into how and where PNH-associated seizures develop. We plan to study a rat model of PNH induced by treating the pregnant dam with methylazoxymethanol (MAM). We will use electrical recording and neuropathological techniques to assess tissue excitability and the functional integrity of the PNH structure and surrounding (and apparently normal) cortex. These procedures will be applied in the intact animal, in acute brain slices, and in organotypic cultures, in order to evaluate both the general circuitry function in cortex containing a PNH-like lesion, and also the properties of individual neurons both within and outside the PNH. In the organotypic slice preparation, we will examine the consequences of removing the PNH (e.g., as a neurosurgeon might do to treat the condition in human brain), in order to assess the efficacy of such manipulations as a function of brain development. PUBLCI

Public Health Relevance

The occurrence of developmentally-based abnormalities in brain structure (e.g., periventricular nodular heterotopia) is commonly associated with seizure disorders i.e., epilepsy and other cognitive deficits. Because we understand relatively little about how this type of structural abnormality gives rise to epilepsy, our ability to treat the epilepsy effectively is limited.
The aim of this proposal is to gain an understanding of the causal relationship between the structural aspects of these disorders and seizures, and to assess the efficacy of surgical removal (at different times during brain development) as a means of therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057209-03
Application #
7799888
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Fureman, Brandy E
Project Start
2008-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$329,176
Indirect Cost
Name
University of California Davis
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Doisy, Emily T; Wenzel, H J├╝rgen; Mu, Yi et al. (2015) Nodule excitability in an animal model of periventricular nodular heterotopia: c-fos activation in organotypic hippocampal slices. Epilepsia 56:626-35
Tschuluun, Naranzogt; Jurgen Wenzel, H; Doisy, Emily T et al. (2011) Initiation of epileptiform activity in a rat model of periventricular nodular heterotopia. Epilepsia 52:2304-14