Repopulated microglia after pharmacological depletion decrease dendritic spine density in adult mouse brain.
Jonathan Wickel1, Ha-Yeun Chung1, Mihai Ceanga1
1Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.
Glia
|May 23, 2024
Summary
Long-term depletion of brain microglia increased synaptic density, but repopulation led to activated microglia, decreased synapses, and impaired neuronal function. Modulating microglia activity may be key for neurological disease therapy.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's innate immune cells, are crucial for synaptic plasticity and neuronal network development.
- Microglia-mediated synaptic pruning contributes to synapse loss in pathological conditions, making them a therapeutic target.
- The impact of microglia depletion and repopulation on adult brain synaptic density and neuronal function remains largely unexplored.
Purpose of the Study:
- To investigate the effects of pharmacological microglia depletion on dendritic spine density and neuronal function.
- To compare outcomes after long-term permanent microglia depletion versus short-term depletion with subsequent repopulation.
Main Methods:
- Utilized colony-stimulating-factor-1 receptor (CSF1-R) inhibitor PLX5622 for microglia depletion in adult mice.
- Assessed dendritic spine density, excitatory postsynaptic current (EPSC) amplitudes, and neuronal function.
- Performed RNA sequencing on repopulated microglia to analyze their phenotype.
- Conducted Barnes maze and elevated plus maze tests to evaluate cognitive and anxiety-like behaviors.
Main Results:
- Long-term microglia depletion increased overall spine density and excitatory postsynaptic current amplitudes.
- Short-term depletion followed by repopulation resulted in activated microglia, increased synaptic phagocytosis, decreased spine density, and reduced excitatory neurotransmission.
- Repopulated microglia exhibited an activated and proinflammatory phenotype via RNA sequencing.
- Behavioral tests (Barnes maze, elevated plus maze) were unaffected by short-term depletion and repopulation.
Conclusions:
- Long-term microglia depletion may offer therapeutic potential for neurological diseases characterized by microglial activation and synapse loss.
- However, microglia repopulation post-depletion induces an activated state, leading to synaptic loss, potentially limiting therapeutic applications.
- Persistent modulation of pathological microglia activity, rather than complete depletion and repopulation, may be a more beneficial strategy for managing synaptic damage.
