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Updated: Aug 29, 2025
Murine Model of Controlled Cortical Impact for the Induction of Traumatic Brain Injury
Published on: August 16, 2019
Ccr2 Gene Ablation Does Not Influence Seizure Susceptibility, Tissue Damage, or Cellular Inflammation after Murine
Rishabh Sharma1, Erskine Chu1, Larissa K Dill1,2
1Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Insights
In pediatric traumatic brain injury (TBI), the CCL2/CCR2 pathway did not worsen seizures or neuroinflammation in young mice. Age may be a key factor in TBI
Area of Science:
- Neuroscience
- Immunology
- Pediatric Traumatology
Background:
- Pediatric traumatic brain injury (TBI) is a significant health concern, potentially leading to post-traumatic epilepsy.
- Research on TBI predominantly focuses on adults, leaving the developing brain's response incompletely understood.
- Neuroinflammation, driven by macrophage infiltration, is implicated in TBI-induced seizures.
Purpose of the Study:
- To investigate the role of C-C motif ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling in neuroinflammation and seizure susceptibility after experimental pediatric TBI.
- To determine if targeting the CCL2/CCR2 pathway could mitigate adverse outcomes in the developing brain following TBI.
Main Methods:
- Utilized the controlled cortical impact (CCI) model in 3-week-old male mice.
- Employed Ccr2 gene-deficient mice and a CCR2 antagonist.
- Assessed seizure susceptibility using pentylenetetrazol (PTZ)-evoked seizures.
- Evaluated cortical tissue loss, neuroinflammation, and oxidative stress.
Main Results:
- TBI increased seizure susceptibility, cortical damage, neuroinflammation, and oxidative stress in young mice.
- Ccr2 deficiency did not worsen seizure susceptibility or neuroinflammation, despite increased serum CCL2.
- CCR2 antagonism did not alter seizure susceptibility or tissue damage in wild-type mice.
Conclusions:
- The CCL2/CCR2 pathway is not a critical driver of epileptogenesis or neuroinflammation in the developing brain after TBI.
- Age appears to be a significant factor, potentially explaining discrepancies with studies in adult models.
- Findings suggest that targeting CCL2/CCR2 may not be an effective strategy for pediatric TBI-related epilepsy.
Abstract:
Pediatric traumatic brain injury (TBI) is a major public health issue, and a risk factor for the development of post-traumatic epilepsy that may profoundly impact the quality of life for survivors. As the majority of neurotrauma research is focused on injury to the adult brain, our understanding of the developing brain's response to TBI remains incomplete. Neuroinflammation is an influential pathophysiological mechanism in TBI, and is thought to increase neuronal hyperexcitability, rendering the brain more susceptible to the onset of seizures and/or epileptogenesis. We here hypothesized that peripheral blood-derived macrophages, recruited into the injured brain via C-C motif ligand 2 (CCL2) chemokine/C-C chemokine receptor type 2 (CCR2) signaling, contributes to neuroinflammation and thus seizure susceptibility after experimental pediatric TBI. Using Ccr2 gene-deficient mice in the controlled cortical impact (CCI) model of TBI, in 3-week-old male mice we found that TBI led to an increase in susceptibility to pentylenetetrazol (PTZ)-evoked seizures, associated with considerable cortical tissue loss, a robust cellular neuroinflammatory response, and oxidative stress. Intriguingly, although Ccr2-deficiency increased CCL2 levels in serum, it did not exacerbate seizure susceptibility or the neuroinflammatory cellular response after pediatric TBI. Similarly, acute post-injury treatment with a CCR2 antagonist did not influence seizure susceptibility or the extent of tissue damage in wild-type (WT) mice. Together, our findings suggest that CCR2 is not a crucial driver of epileptogenesis or neuroinflammation after TBI in the developing brain. We propose that age may be an important factor differentiating our findings from previous studies in which targeting CCL2/CCR2 has been reported to be anti-inflammatory, neuroprotective or anti-seizure.
