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Updated: May 1, 2026
Primary Microglia Isolation from Mixed Glial Cell Cultures of Neonatal Rat Brain Tissue
Published on: August 15, 2012
Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission
Youichi Shinozaki1, Masatoshi Nomura2, Ken Iwatsuki3
11] Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
Abstract:
Microglia are highly sensitive to even small changes in the brain environment, such as invasion of non-hazardous toxicants or the presymptomatic state of diseases. However, the physiological or pathophysiological consequences of their responses remain unknown. Here, we report that cultured microglia sense low concentrations of the neurotoxicant methylmercury (MeHg(low)) and provide neuroprotection against MeHg, for which astrocytes are also required. When exposed to MeHg(low), microglia exocytosed ATP via p38 MAPK- and vesicular nucleotide transporter (VNUT)-dependent mechanisms. Astrocytes responded to the microglia-derived ATP via P2Y1 receptors and released interleukin-6 (IL-6), thereby protecting neurons against MeHg(low). These neuroprotective actions were also observed in organotypic hippocampal slices from wild-type mice, but not in slices prepared from VNUT knockout or P2Y1 receptor knockout mice. These findings suggest that microglia sense and respond to even non-hazardous toxicants such as MeHg(low) and change their phenotype into a neuroprotective one, for which astrocytic support is required.
Insights
Microglia protect neurons from methylmercury (MeHg) by releasing ATP, which signals astrocytes to produce interleukin-6. This astrocyte-neuron communication, involving vesicular nucleotide transporter (VNUT) and P2Y1 receptors, offers neuroprotection.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Microglia, the brain's immune cells, are sensitive to environmental changes.
- The functional outcomes of microglial responses to subtle brain alterations are not fully understood.
Purpose of the Study:
- To investigate the consequences of microglial sensing of low-dose methylmercury (MeHg(low)).
- To elucidate the mechanisms of neuroprotection against MeHg involving microglia and astrocytes.
Main Methods:
- Primary microglia and astrocyte co-cultures.
- Organotypic hippocampal slice cultures from wild-type and knockout mice (VNUT, P2Y1 receptor).
- Measurement of ATP release, IL-6 production, and neuronal survival.
Main Results:
- Microglia exposed to MeHg(low) released ATP via p38 MAPK and VNUT.
- Astrocytes responded to microglial ATP via P2Y1 receptors, releasing IL-6.
- This signaling pathway conferred neuroprotection against MeHg(low) in both cultures and brain slices.
Conclusions:
- Microglia sense and respond to low concentrations of toxicants like MeHg.
- A cooperative mechanism between microglia and astrocytes, mediated by ATP and IL-6, provides neuroprotection.
- This pathway is crucial for mitigating MeHg-induced neurotoxicity.
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