Neurogenesis persists in the hippocampal dentate gyrus and is proposed as a critical factor underlying hyperexcitability in mesial temporal lobe epilepsy (mTLE). In most rodent mTLE models, status epilepticus (SE) stimulates adult dentate granule cell (DGC) neurogenesis but leads to aberrant integration of a subset of new neurons that is implicated in epileptogenesis, as well as cognitive and mood-related co-morbidities. However, whether the net effect of adult neurogenesis is pro- or anti-epileptogenic remains controversial. The long-term goals of our work are to determine the factors regulating adult neurogenesis in the intact and epileptic hippocampus, to establish whether aberrant neurogenesis is critical for epileptogenesis and associated co-morbidities, and to develop therapeutic strategies for preventing aberrant neuronal integration after brain insults. The objectives of this proposal are to 1) understand how adult-born vs. neonatal-born DGCs structurally and functionally integrate into intact and epileptic networks; and 2) determine the role adult-born DGCs play in the development of epilepsy and cognitive co-morbidities in experimental mTLE. We are applying innovative methods for examining neuronal integration and circuit function to the study of adult neurogenesis in mTLE models, including retroviral (RV) synaptic reporter labeling, rabies virus (RbV) tracing and optogenetic activation of pre-synaptic inputs, and neuronal silencing with DREADDs (Designer Receptors Activated by Designer Drugs). Our preliminary data from synaptic reporter labeling and dual virus (RV and RbV) retrograde trans-synaptic tracing suggests that both the projections and synaptic inputs of adult-born DGCs are altered after SE compared to DGCs in the intact brain or those born neonatally prior to SE in adulthood. Moreover, our in vitro recordings of RV-birthdated DGCs show that aberrantly integrated, adult-born DGCs receive excessive excitatory input after SE, implicating them as potential hub cells for epileptogenesis. We are also breeding conditional DREADD mice that allow for the reversible chemical silencing of adult-born neurons. Thus, we now have the tools to precisely define the integration of birthdated DGCs during epileptogenesis, and to silence their activity on demand. We propose to use these cutting edge approaches to test the hypothesis that seizure- induced neurogenesis is a critical component of epileptogenesis and associated hippocampal learning deficits due to the aberrant integration of adult-born neurons into recurrent excitatory circuitry. We will test this hypothesis by pursuing three specific aims: 1) To determine how seizure-induced network remodeling alters the neuroanatomical connections of adult-born vs. neonatal-born DGCs; 2) To establish how birthdate and morphological abnormalities impact DGC excitability and network influences in the epileptic hippocampus; and 3) To determine whether reversibly silencing adult-born DGCs will attenuate seizures in the mouse pilocarpine mTLE model. Progress in these experiments will advance our understanding of mechanisms underlying mTLE and a critical co-morbidity, and should offer insight into gene therapy approaches for epilepsy.

Public Health Relevance

Up to 3 million persons in the U.S. have epilepsy, over 30% without adequate seizure control on medications, and temporal lobe epilepsy (TLE) is among the most common forms of drug-resistant epilepsy. Neural stem cells and the birth of new neurons persists into adulthood in the hippocampus and their dysregulation is implicated in TLE. These studies will determine the abnormal brain circuitry generated by the aberrant development of neural stem cells after a brain insult in rodent TLE models, and whether silencing adult-born neurons will attenuate epilepsy and associated learning dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058585-10
Application #
9625662
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Leenders, Miriam
Project Start
2009-09-28
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
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
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