# The STAT3 Response of Excitatory Neurons to Epileptogenic Brain Injury

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $638,994

## Abstract

Abstract
Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades
and neural circuit remodeling in the hippocampus resulting in increased susceptibility to spontaneous seizures
and cognitive dysfunction. Targeting these cascades could prevent or reverse symptom progression and has the
potential to provide viable disease-modifying treatments that could reduce the portion of TLE patients (>30%)
not responsive to current medical therapies. The Janus Kinase/Signal Transducer and Activator of Transcription
(JAK/STAT) pathway has recently been implicated in the pathogenesis of TLE. This pathway is known to be
involved in inflammation and immunity, and to be critical for neuronal functions such as synaptic plasticity and
synaptogenesis. Our laboratories previously showed that a STAT3 inhibitor, WP1066, could greatly reduce the
number of spontaneous recurrent seizures (SRS) in an animal model of pilocarpine-induced status epilepticus
(SE). While this suggests promise for JAK/STAT inhibitors as disease-modifying therapies, the potential adverse
effects of systemic or global CNS pathway inhibition limits their use. Development of more targeted therapeutics
will require a detailed understanding of JAK/STAT-induced epileptogenic responses in different cell types. To
this end, we have developed a new transgenic line where dimer-dependent STAT3 signaling is functionally
knocked out (fKO) by tamoxifen-induced Cre expression specifically in forebrain excitatory neurons (eNs) via the
Calcium/Calmodulin Dependent Protein Kinase II alpha (CamK2a) promoter. We now report that STAT3 KO in
excitatory neurons (eNSTAT3fKO) markedly reduces the progression of epilepsy (SRS frequency) in the
intrahippocampal kainate (IHKA) TLE model and protects mice from kainic acid (KA)-induced memory deficits
as assessed by Contextual Fear Conditioning. Using data from bulk hippocampal tissue RNA-sequencing, we
further discovered a transcriptomic signature for the IHKA model that contains a substantial number of genes,
particularly in synaptic plasticity and inflammatory gene networks, that are down-regulated after KA-induced SE
in wild-type but not eNSTAT3fKO mice. In this application, we will test the hypothesis that STAT3 signaling in
excitatory neurons is a key driver of epilepsy progression via the selective silencing of genes that regulate
synaptic plasticity and neuroinflammation. With an integration of open discovery using multiomics and
quantitative molecular imaging (Aims 1 and 3), in combination with electrophysiology and neuropharmacology
(Aim 2), we will elucidate the genome’s response to injury (24 h and 4 wks after IHKA) within different cell types
and determine why STAT3 KO in eNs inhibits disease progression after KA injection by identifying direct and
indirect effects of loss of eNSTAT3 expression on both excitatory and inhibitory neurons. We will also determine
the relationship between eNSTAT3 signaling and glial a...

## Key facts

- **NIH application ID:** 10833109
- **Project number:** 5R01NS122385-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Amy R. Brooks-Kayal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $638,994
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833109

## Citation

> US National Institutes of Health, RePORTER application 10833109, The STAT3 Response of Excitatory Neurons to Epileptogenic Brain Injury (5R01NS122385-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10833109. Licensed CC0.

---

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