# Role of deltaFosB in hippocampal gene expression and function in neurological disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $594,609

## Abstract

Project Summary
Cognitive impairment is a devastating co-morbidity of conditions with recurrent seizures, such as Alzheimer's
disease and epilepsy, which persists even in seizure-free periods. We recently published that one critical
reason for this is that seizures induce dentate gyrus (DG) expression of ∆FosB, a transcription factor that
epigenetically suppresses key target genes that are crucial for plasticity and memory. ∆FosB expression is
associated with cognitive deficits in patients and mouse models of epilepsy as well as Alzheimer's disease,
demonstrating common mechanisms of cognitive dysfunction in conditions with seizures. Our new studies
indicate ∆FosB acts on more than memory-related genes; it also represses genes that enhance intrinsic
excitability, and thereby limits overall DG excitability. These findings indicate that seizure-induced ∆FosB
expression is a “double-edged sword” that caps DG excitability, but at the cost of plasticity and cognitive
function. Our goals are to build a comprehensive understanding of functional domains regulated by ∆FosB in
the hippocampus, and identify novel strategies to improve cognition but maintain regulation of neuronal
excitability in conditions with seizures, such as Alzheimer's disease and epilepsy. We previously used
hypothesis-driven approaches to identify ∆FosB targets in hippocampus, but it was necessary to also obtain an
unbiased, comprehensive view of ∆FosB in seizure-related conditions. To do so, we performed ChIP-
sequencing to identify all genes bound by ∆FosB in the hippocampus of a well-characterized transgenic mouse
model of Alzheimer's disease (AD mice) that exhibits recurrent seizures and high ∆FosB levels. In AD mice,
∆FosB bound to a novel network of genes involved in multiple aspects of neuronal excitability. Many of these
genes were also bound by ∆FosB in hippocampus of wild-type mice treated with pilocarpine, a
pharmacological model of epilepsy. In wild-type mice, AAV-mediated overexpression of ∆FosB decreased
excitability whereas ∆JunD, a dominant negative antagonist of ∆FosB, increased excitability. Notably, long-
term blockade of ∆FosB signaling in DG of AD mice changed the phenotype of their seizures from primarily
nonconvulsive to primarily convulsive, supporting the theory that the typically low excitability and sparse
activation of DG cells acts as a filter or gate that restricts epileptogenesis. Our work indicates ∆FosB plays
critical roles in neuronal function in conditions with recurrent seizures. Understanding the mechanisms by
which ∆FosB coordinately regulates expression of genes that control synaptic plasticity or neuronal excitability
may reveal novel therapeutic strategies to reduce epileptogenesis while improving cognition. To this end, we
will examine both Alzheimer's mice and pilocarpine mice to: 1) Investigate the role of ∆FosB in controlling
intrinsic and network excitability of the DG, 2) identify and characterize the repertoire of hippocampal genes
targ...

## Key facts

- **NIH application ID:** 10189710
- **Project number:** 5R01NS085171-09
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** JEANNIE CHIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $594,609
- **Award type:** 5
- **Project period:** 2014-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189710

## Citation

> US National Institutes of Health, RePORTER application 10189710, Role of deltaFosB in hippocampal gene expression and function in neurological disease (5R01NS085171-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189710. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*