# A role for the complement system in seizure induced neuronal and dendritic injury

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $333,878

## Abstract

Project Summary
Epilepsy is a seizure disorder that is often comorbid with cognitive disabilities. Prolonged-continuous seizures
(status epilepticus; SE) increase the risk for the development of temporal lobe epilepsy (TLE) by remodeling
synaptic connectivity in vulnerable neuronal networks such as those of the hippocampus. Extensive evidence
supports that SE-induced hippocampal synaptodendritic remodeling orchestrated through glutamate
excitotoxicity, apoptosis, and aberrant activation from a number of intracellular signaling cascades is linked to
the neuronal hyperexcitability that often results in seizures. Despite these findings, the mechanisms that
directly impact neural hyperexcitability remain elusive. A prominent hallmark in the histopathology of SE and
epilepsy is activation of microglia, which mediate neuroinflammatory and phagocytic responses. It is well
known that microglia-mediated neuroinflammatory mechanisms contribute to seizures; however, a gap remains
on the potential role of their phagocytic responses. During and after SE microglia make multiple physical
contacts with cortical and hippocampal dendrites, a phenomenon that we recently found in human refractory
epilepsy. These contacts may result in the phagocytosis of dendritic structures and thereby modification of
neuronal connectivity. Recent studies discovered that C1q and C3 proteins from the immune complement
system send “eat-me” signals that guide microglia to phagocytose extranumerary synapses in the normal
developing brain. In addition, C1q and C3 are associated with the pathological removal of hippocampal
synaptic structures in models of neurodegenerative disorders. We and others found increases in C1q-C3
mRNA and protein levels in intractable human epilepsy and after SE in experimental models. Therefore, we
hypothesized that seizure-induced activation of the immune complement system contributes to hippocampal
synaptodendritic modifications that promote neuronal/network hyperexcitability, seizures, and memory deficits.
We will pursue the following Aims, Aim1: To characterize complement activation and associated responses in
a mouse model of SE and TLE; Aim2: To determine the contribution of SE-induced C3 activation to neuronal
and synaptodendritic changes in the hippocampus in a mouse model of TLE; Aim3: To determine the
contribution of SE-induced C3 activation to seizures and hippocampal-dependent memory deficits in a mouse
model of TLE. This study will provide a strong framework for understanding the phagocytic role of the innate
immune complement system and microglia in the SE-induced generation of epileptic circuits. Our scientific
discoveries are likely to provide evidence for the potential therapeutic value of directly modulating the
complement cascade to attenuate seizures and cognitive comorbidities in epilepsy. Importantly, because FDA-
approved complement inhibitors are currently being used for immunological illnesses in humans, our study
may provide evidence ...

## Key facts

- **NIH application ID:** 9898484
- **Project number:** 5R01NS096234-02
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Amy L. Brewster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,878
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898484

## Citation

> US National Institutes of Health, RePORTER application 9898484, A role for the complement system in seizure induced neuronal and dendritic injury (5R01NS096234-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898484. Licensed CC0.

---

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