Mesial temporal lobe epilepsy (mTLE) is a common epilepsy syndrome that typically manifests with pharmacoresistant seizures. Histopathology in human and experimental mTLE shows hippocampal pyramidal and dentate hilar neuron loss, dentate granule cell (DGC) layer dispersion, and DGC axonal remodeling known as mossy fiber sprouting (MFS). Recent work has uncovered additional pathology involving DGCs in experimental mTLE: persistent hilar basal dendrites (HBDs) and DGCs in ectopic locations in the hilus and molecular layer. Remarkably, these abnormalities arise from disordered neurogenesis, as DGC neurogenesis persists throughout life. These findings have led to the idea that epileptogenic insults result in the aberrant integration of newborn DGCs. This idea is supported by morphological and electrophysiological evidence that aberrant neurogenesis induces network hyperexcitability. Other work, in contrast, suggests that normally integrated adult-born DGCs compensate for epileptogenic hyperexcitability by restoring inhibition after status epilepticus (SE)-induced injury. Using the rat pilocarpine epilepsy model, we recently discovered that only developing, and not mature, DGCs are responsible for abnormal DGC plasticity during epileptogenesis, including MFS and the presence of HBDs and ectopic DGCs. Data from our lab and others also suggest that reduced expression of the secreted developmental cue reelin in epileptic hippocampus contributes to aberrant neuroblast migration in experimental mTLE, and DGC layer dispersion in human mTLE. Based on these data, we propose to test the following hypotheses: 1) Only DGCs not fully mature at the time of injury or those generated after injury are vulnerable to SE-induced plasticity, and loss of dentate gyrus reelin expression underlies some forms of this plasticity;and 2) Most vulnerable DGCs or their progenitors integrate abnormally during epileptogenesis, leading to hippocampal hyperexcitability and seizures;blocking neurogenesis or aberrant DGC integration therefore will ameliorate the epileptic state. We propose 3 specific aims to test these hypotheses.
Aim 1 is to determine whether altered reelin signaling leads to aberrant DGC progenitor migration or HBD formation in the intact or epileptic dentate gyrus.
Aim 2 is to characterize the vulnerability of DGCs at different developmental stages (ranging from mature at SE to those born after SE) to SE-induced plasticity, and to examine intrinsic properties and network influences of developing DGCs integrating normally or aberrantly during epileptogenesis.
In Aim 3, we propose to determine whether attenuating aberrant integration of developing DGCs will suppress epileptogenesis. Progress in these aims will provide insight into the regulation of adult neurogenesis, will determine the functional role of aberrant neurogenesis in epilepsy, and may lead to novel therapeutic strategies to inhibit epileptogenesis or cognitive impairment in mTLE.

Public Health Relevance

Temporal lobe epilepsy (TLE) is a common epilepsy that is often resistant to antiepileptic medications and requires surgical therapy. Patients are typically disabled by frequent seizures and associated memory impairment. We have evidence that injury leading to experimental TLE induces adult hippocampal neural stem cells to generate misplaced and abnormal new nerve cells. We propose to determine the mechanisms underlying the neural stem cell alterations and whether normalizing their behavior blocks epilepsy development. Progress in this area therefore may offer novel treatments to prevent TLE after brain insults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058585-05
Application #
8516601
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Fureman, Brandy E
Project Start
2009-09-28
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$392,165
Indirect Cost
$131,253
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Brackenbury, William J; Yuan, Yukun; O'Malley, Heather A et al. (2013) Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b-null mice and precedes hyperexcitability. Proc Natl Acad Sci U S A 110:1089-94