# Identification and reversal of primary and secondary epileptogenic changes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $486,278

## Abstract

Project Summary/Abstract
 Elucidating the basic mechanisms by which a normal brain is transformed into an epileptic brain has
been a holy grail of epilepsy research for decades. If the mechanisms of epileptogenesis can be understood,
then new treatments and therapies can be designed to target these processes to prevent – and possibly cure –
epilepsy. While years of research have revealed a multitude of changes that occur during epileptogenesis, one
basic problem has been distinguishing changes that mediate epileptogenesis from changes that are associated
with the disease, but play no causal role. This problem is evident for almost all existing models of epilepsy,
which produce widespread brain damage and cellular changes, thereby making the proximal cause of the
disease difficult to ascertain. For the present proposal, we utilize a novel mouse model of epilepsy generated in
the first term of this grant, in which spontaneous cortical seizures develop following conditional, inducible
deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from >9% of hippocampal
dentate granule cells. The effect of this deletion – to induce the abnormal integration of newborn granule cells
– is important because abnormal newborn granule cells are a hallmark pathology of temporal lobe epilepsy,
and are suspected of causing the disease. Our model provides direct evidence that abnormal granule cells can
cause epilepsy, and creates an opportunity to understand how they cause the disease.
Work with this model has led us to hypothesize that spontaneous seizures in temporal lobe epilepsy
result from the combinatorial effects of intrinsically hyperexcitable granule cells and impaired inhibitory control
of these cells. To test this two-hit model of epileptogenesis, we will make full use of a unique feature of our
PTEN knockout model: the ability to manipulate the number or “load” of abnormal granule cells. We will
generate animals in which 5-8% of granule cells lack PTEN. These animals exhibit abnormal hippocampal
physiology, but not overt cortical seizures. This constitutes the first “hit”. We will then challenge these altered
circuits by silencing distinct classes of hippocampal inhibitory interneurons in vitro and in vivo – the second hit.
We predict that disinhibition will act synergistically with PTEN knockout granule cells to destabilize the
hippocampal circuit and promote seizures. The studies will provide a proof-of-concept test for how temporal
lobe epilepsy develops, and will provide insights into therapeutic strategies.

## Key facts

- **NIH application ID:** 9925829
- **Project number:** 5R01NS065020-12
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Steve C Danzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,278
- **Award type:** 5
- **Project period:** 2009-05-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925829

## Citation

> US National Institutes of Health, RePORTER application 9925829, Identification and reversal of primary and secondary epileptogenic changes (5R01NS065020-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9925829. Licensed CC0.

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