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Updated: Dec 12, 2025
Author Spotlight: In Vitro Co-Culture Model for Studying Microglia-Neuronal Interactions in Disease Conditions
Published on: July 26, 2024
GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ
Hasan Onur Dikmen1, Marc Hemmerich1, Andrea Lewen1
1Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
Background:
The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the consequent impacts on neuronal survival, excitability, and synaptic transmission are widely unknown, however. Here, we focused on electrical neuronal network rhythms in the gamma frequency band (30-70 Hz). Gamma oscillations are fundamental to higher brain functions, such as perception, attention, and memory, and they are exquisitely sensitive to metabolic and oxidative stress.
Methods:
We explored the effects of chronic GM-CSF exposure (72 h) on microglia in male rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortex tissue lacking leukocyte invasion (adaptive immunity). We applied extracellular electrophysiological recordings of local field potential, immunohistochemistry, design-based stereology, biochemical analysis, and pharmacological ablation of microglia.
Results:
GM-CSF triggered substantial proliferation of microglia (microgliosis). By contrast, the release of proinflammatory cytokines (IL-6, TNF-α) and nitric oxide, the hippocampal cytoarchitecture as well as the morphology of parvalbumin-positive inhibitory interneurons were unaffected. Notably, GM-CSF induced concentration-dependent, long-lasting disturbances of gamma oscillations, such as slowing (beta frequency band) and neural burst firing (hyperexcitability), which were not mimicked by the T lymphocyte cytokine IL-17. These disturbances were attenuated by depletion of the microglial cell population with liposome-encapsulated clodronate. In contrast to priming with the cytokine IFN-γ (type II interferon), GM-CSF did not cause inflammatory neurodegeneration when paired with the TLR4 ligand LPS.
Conclusions:
GM-CSF has a unique role in the activation of microglia, including the potential to induce neuronal network dysfunction. These immunomodulatory properties might contribute to cognitive impairment and/or epileptic seizure development in disease featuring elevated GM-CSF levels, blood-brain barrier leakage, and/or T cell infiltration.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) activates microglia, causing neuronal network dysfunction. This may contribute to cognitive impairment and seizures in diseases with high GM-CSF.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) is involved in myeloid cell differentiation and inflammation.
- The role of GM-CSF in microglia activation and its impact on neuronal function is largely unknown.
- Gamma oscillations are crucial for cognitive functions and sensitive to cellular stress.
Purpose of the Study:
- To investigate the effects of GM-CSF on microglia and neuronal network activity.
- To explore GM-CSF's role in modulating gamma oscillations in the hippocampus.
Main Methods:
- Organotypic hippocampal slice cultures from male rats were chronically exposed to GM-CSF.
- Electrophysiological recordings, immunohistochemistry, stereology, and biochemical analyses were performed.
- Microglia were pharmacologically ablated to assess their role in GM-CSF-induced effects.
Main Results:
- GM-CSF induced significant microglial proliferation (microgliosis) without altering cytokine release or neuronal morphology.
- GM-CSF caused concentration-dependent, long-lasting disturbances in gamma oscillations, including slowing and hyperexcitability.
- These network disturbances were reduced by microglial depletion and not mimicked by IL-17.
Conclusions:
- GM-CSF uniquely activates microglia, leading to potential neuronal network dysfunction.
- These findings suggest GM-CSF's immunomodulatory properties may contribute to cognitive deficits and epilepsy.
- Elevated GM-CSF levels in diseases could link neuroinflammation to neurological disorders.
