Temporal lobe epilepsy (TLE) develops in a third of over 300,000 patients with a first seizure and over 30% of cases are resistant to drugs contributing to a significant disability. Presence of a therapeutic time window between the initial insult and development of epilepsy suggests that improved mechanistic understanding of early pathological process may enable prevention of epileptogenesis and associated co-morbidities. While sclerosis of the hippocampal dentate gyrus characterizes late stage TLE, cell loss, network reorganization and deficient inhibition in the dentate gyrus occur soon after insults that progress to TLE. In particular, the dentate inhibitory gate which limits GC activity throughput is compromised early in acquired TLE. However, what cells and circuits make up the dentate inhibitory gate and how this is compromised after seizures is not fully understood. Recently, a new class of neurons, semilunar granule cells (SGCs) were proposed as drivers of sustained dentate feedback inhibition. Although SGC-like neuros are observed in multiple species including humans and are activated during behaviors, the development, molecular identity, and connectivity of SGCs are not known making it difficult to determine their role in dentate function and disease. The limited literature and our pilot data that SGCs input and output connections are distinct from granule cells indicating that they play a unique role in dentate processing. This study will test the hypothesis that SGCs from a parallel dentate circuit that strengthens inhibition in the normal brain. We further propose that cellular and network changes after seizures compromise SGC mediated inhibition and augment their excitatory effects contributing to epilepsy and memory deficits. Combining morphometry, Patch-seq transcriptomics, electro- and optophysiology in transgenic mouse lines subject to experimental epilepsy and computational modeling will allow us to test the above hypothesis.
Aim 1 will define the cellular and circuit identity of SGCs and determine molecular markers.
Aim 2 will determine if the SGC excitatory circuit is strengthened and feedback inhibitory circuit compromised after status epilepticus. Finally, Aim 3 will examine the normal and seizure-induced development of SGCs and their contribution to dentate memory processing. On completion the studies will eliminate specific knowledge gaps in how the dentate circuit functions in behaviors and epilepsy, in keeping with the NINDS mission, and provide information needed to prevent collapse of dentate inhibition soon after seizures and prevent development of epilepsy and memory co-morbidities.

Public Health Relevance

There are over 100,000 new cases of temporal lobe epilepsy annually a third of which are resistant to treatments underscoring the need to target epileptogenesis and prevent epilepsy. Experiments proposed here test a novel hypothesis on regulation of inhibition in the dentate gyrus which is compromised following insults leading to epilepsy. The knowledge developed will provide novel tools to modify behaviors, prevent collapse of the dentate gate and reduce memory co-morbidities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069861-09
Application #
9712965
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Churn, Severn Borden
Project Start
2011-09-30
Project End
2023-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Anatomy/Cell Biology
Type
Earth Sciences/Resources
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
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