Temporal lobe epilepsy is the most prevalent and least therapeutically responsive form of epilepsy in the adult population. In addition to the spontaneous seizures that define the condition, temporal lobe epilepsy is associated with significant cognitive and emotional comorbidities, and this triad of symptoms defines its devastating consequences in patients. Clearly, based on its prevalence, distressing symptomology, and lack of adequate control by existing medications, a better mechanistic understanding of this disorder is critical in improving this dire clinical outlook. Many hippocampal alterations are associated with temporal lobe epilepsy development, with the most prevalent being pathologic hyperactivation of the dentate gyrus. Although these diverse hippocampal circuit changes accompany the clinical condition, which disruptions causally contribute to the symptoms underlying epilepsy is not known. To determine this, it is necessary to move beyond observational studies and to evaluate a causal linkage. This can be accomplished by reversing a specific circuit change experimentally and looking for restorative effects on seizure susceptibility, cognition, and emotional state?proving a change is necessary for full manifestation of epilepsy. Similarly, it is also essential to establish that mimicking the circuit change in normal animals (in the absence of any other alteration) is able to induce the same set of hallmark epilepsy symptoms?proving that a change is sufficient to generate changes in seizure predisposition, cognition, and emotional state. Our CENTRAL HYPOTHESIS driving the research in this application is that epilepsy-associated dentate gyrus hyperexcitability generates the enhanced seizure susceptibility, disrupted cognition, and emotional disturbances that are the hallmark symptoms of epilepsy. We plan to test this hypothesis through experiments centered on 3 AIMS.
These aims are:
AIM 1 : Determine the role played by epilepsy-associated dentate granule cell hyperexcitability in generation of the elevated seizure susceptibility underlying both the development and expression of epilepsy.
AIM 2 : Characterize the role played by epilepsy-associated dentate granule cell hyperexcitability in compromised cognitive performance and elevated anxiety in an animal model of temporal lobe epilepsy.
AIM 3 : Assess the role played by epilepsy-associated dentate granule cell hyperexcitability in deficient spatial encoding in the hippocampus. Dentate gyrus hyperexcitability is seen both in animal models as well as in patients. Successful completion of this proposed research should provide a definitive assessment of the role played by this prevalent epilepsy-associated circuit disruption in the generation of the core triad of epilepsy symptoms. Understanding the causal contributions of circuit changes generating epilepsy is critical in understanding the key processes mediating epilepsy development, which in turn is necessary in developing new therapies to more effectively alleviate epilepsy symptoms, and potentially cure this devastating disorder.

Public Health Relevance

Temporal lobe epilepsy is among the most prevalent and least therapeutically responsive variants of epilepsy, and its debilitating symptoms, including seizures, cognitive problems, and emotional disturbances, combine to impose a significant health burden, which could benefit from improved treatment options. However, the pathogenic mechanisms underlying temporal lobe epilepsy are poorly understood, limiting the development of new therapies. This proposal focuses on determining how specific hippocampal circuits may contribute to the symptoms of temporal lobe epilepsy, with a goal of better understanding this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038572-18
Application #
9861266
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Churn, Severn Borden
Project Start
1999-05-06
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
18
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146
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