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Updated: Mar 21, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression
Tsubasa Takizawa1, Mamoru Shibata1, Yohei Kayama1
11 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Insights
Multiple cortical spreading depression (CSD) episodes activate microglia via the HMGB1-TLR2/4 pathway, impacting gene transcription and potentially phagocytic activity. This highlights a novel mechanism in brain injury responses.
Area of Science:
- Neuroscience
- Cellular Biology
- Pathophysiology
Background:
- Cortical spreading depression (CSD) is linked to migraine aura and brain injury.
- High-mobility group box 1 (HMGB1) release after CSD depends on episode frequency.
- HMGB1 is implicated in neuroinflammation and neuronal damage.
Purpose of the Study:
- To investigate the role of multiple CSD episodes in microglial activation.
- To elucidate the involvement of the HMGB1-TLR2/4 axis in CSD-induced microglial responses.
- To explore downstream effects on gene transcription and lysosomal activity.
Main Methods:
- Rodent model of multiple cortical spreading depression (CSD) inductions.
- Administration of HMGB1-neutralizing antibody and glycyrrhizin.
- Analysis of microglial morphology and gene transcription.
- Utilized TLR2/4 double knockout mice.
Main Results:
- Multiple CSD inductions, but not single episodes, caused microglial hypertrophy (activation).
- HMGB1-neutralizing antibody and glycyrrhizin inhibited CSD-induced microglial hypertrophy.
- Microglial activation was absent in TLR2/4 double knockout mice.
- Increased cathepsin D expression suggests enhanced lysosomal activity in activated microglia.
Conclusions:
- The HMGB1-TLR2/4 axis is crucial for microglial activation following multiple CSD episodes.
- Multiple CSD inductions lead to specific microglial activation patterns, distinct from single CSD events.
- This pathway may represent a therapeutic target for CSD-related brain conditions.
Abstract:
Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1-TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.
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