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Updated: Aug 10, 2026
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 7, 2017
Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus
1MSTP Program, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651, USA.
Background:
Injury to the brain induces dramatic local changes in gene expression, cellular morphology and behavior. Activation of microglial cells occurs as an early event after central nervous system (CNS) injury, but it has not been determined whether such activation plays a causal role in neuronal death. We have investigated this question using an excitotoxin-mediated brain injury model system, in conjunction with an endogenous peptide factor (macrophage/microglial inhibiting factor, MIF) that ablates microglial contribution to the cascade.
Results:
Using MIF, we inhibited the microglial activation that normally follows excitotoxic injury. In cell culture studies, we found that such inhibition blocked the rapid release of microglia-derived tissue plasminogen activator (tPA), an extracellular serine protease made by both neurons and microglia, which we had previously identified as mediating a critical step in excitotoxin-induced neuronal death. Finally, infusion of MIF into the mouse brain prior to excitotoxic insult resulted in the protection of neurons from cell death.
Conclusions:
Our results demonstrate that microglia undertake a neurotoxic role when excitotoxic injury occurs in the CNS. They also suggest that the tPA released from microglia has a critical role in triggering neurodegeneration.
Insights
Microglia activation contributes to brain damage after injury. Inhibiting this process with macrophage/microglial inhibiting factor (MIF) protected neurons by blocking tissue plasminogen activator (tPA) release, suggesting a neurotoxic role for microglia.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Central nervous system (CNS) injury triggers significant changes in gene expression and cell morphology.
- Microglial cell activation is an early response to CNS injury, but its role in neuronal death remains unclear.
- Excitotoxic brain injury models are used to study neuroinflammation and neuronal death.
Purpose of the Study:
- To investigate the causal role of microglial activation in excitotoxin-induced neuronal death.
- To determine if inhibiting microglial activation can prevent neuronal death.
- To elucidate the mechanisms by which microglia contribute to neurodegeneration.
Main Methods:
- Utilized an excitotoxin-mediated brain injury model in mice.
- Employed macrophage/microglial inhibiting factor (MIF) to block microglial activation.
- Conducted cell culture studies to assess the release of tissue plasminogen activator (tPA).
- Administered MIF intracerebrally prior to excitotoxic insult.
Main Results:
- Inhibition of microglial activation using MIF prevented the release of microglia-derived tissue plasminogen activator (tPA).
- Cell culture experiments confirmed that blocking microglial activation halted tPA release.
- Intracerebral infusion of MIF protected neurons from excitotoxic cell death in vivo.
- This suggests microglia play a neurotoxic role following CNS injury.
Conclusions:
- Microglia play a detrimental, neurotoxic role in the context of excitotoxic CNS injury.
- The release of tissue plasminogen activator (tPA) from activated microglia is a critical factor in excitotoxin-induced neurodegeneration.
- Targeting microglial activation represents a potential therapeutic strategy for CNS injury.
