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Axon initial segment-associated microglia
Kelli Baalman1, Miguel A Marin1, Tammy Szu-Yu Ho2
1Department of Neuroscience.
Abstract:
Microglia are the brain's resident immune cells and function as the main defense against pathogens or injury. However, in the absence of disease, microglia have other functions in the normal brain. For example, previous studies showed that microglia contribute to circuit refinement and synaptic plasticity in the developing and adult brain, respectively. Thus, microglia actively participate in regulating neuronal excitability and function. Here, we report that in the cortex, but not other brain regions, a subset of microglia extend a single process that specifically associates and overlaps with the axon initial segment (AIS), the site where action potentials are generated. Similar associations were not observed with dendrites or distal axons. Microglia-AIS interactions appear early in development, persist throughout adulthood, and are conserved across species including mice, rats, and primates. However, these interactions are lost after microglial activation following brain injury, suggesting that such interactions may be part of healthy brain function. Loss of microglial CX3CR1 receptors, or the specialized extracellular matrix surrounding the AIS, did not disrupt the interaction. However, loss of AIS proteins by the neuron-specific deletion of the master AIS scaffold AnkyrinG disrupted microglia-AIS interactions. These results reveal a unique population of microglia that specifically interact with the AIS in the adult cortex.
Insights
Microglia, the brain's immune cells, form unique connections with the axon initial segment (AIS) in the cortex. This interaction is vital for healthy brain function and is disrupted by injury.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are resident immune cells in the brain, crucial for defense against pathogens and injury.
- Beyond immune functions, microglia play roles in synaptic plasticity and circuit refinement in the healthy brain.
- Microglia actively regulate neuronal excitability and function.
Purpose of the Study:
- To investigate novel functions of microglia in the healthy adult brain.
- To identify specific interactions between microglia and neuronal structures.
- To characterize the nature and regulation of microglia-axon initial segment (AIS) interactions.
Main Methods:
- High-resolution microscopy to visualize microglia-neuronal interactions in different brain regions.
- Comparative analysis across species (mice, rats, primates) and developmental stages.
- Genetic manipulation to assess the role of specific molecules (CX3CR1, AnkyrinG) and extracellular matrix in microglia-AIS interactions.
Main Results:
- A subset of cortical microglia extends a single process that specifically associates with the axon initial segment (AIS).
- These microglia-AIS interactions are observed in the cortex but not other brain regions, are present from development through adulthood, and are conserved across species.
- Interactions are lost upon microglial activation (e.g., after brain injury) but are independent of CX3CR1 and AIS extracellular matrix.
- Disruption of AnkyrinG, a master AIS scaffold protein, abolishes microglia-AIS interactions.
Conclusions:
- A unique population of microglia specifically interacts with the AIS in the adult cortex.
- These microglia-AIS interactions are a feature of healthy brain function and are dependent on AIS structural components.
- The findings reveal a novel role for microglia in regulating neuronal function at the AIS.
