Microglial process convergence on axonal segments in health and disease

Abstract

Microglia dynamically interact with neurons influencing the development, structure, and function of neuronal networks. Recent studies suggest microglia may also influence neuronal activity by physically interacting with axonal domains responsible for action potential initiation and propagation. However, the nature of these microglial process interactions is not well understood. Microglial-axonal contacts are present early in development and persist through adulthood, implicating microglial interactions in the regulation of axonal integrity in both the developing and mature central nervous system. Moreover, changes in microglial-axonal contact have been described in disease states such as multiple sclerosis (MS) and traumatic brain injury (TBI). Depending on the disease state, there are increased associations with specific axonal segments. In MS, there is enhanced contact with the axon initial segment and node of Ranvier, while, in TBI, microglia alter interactions with axons at the site of injury, as well as at the axon initial segment. In this article, we review the interactions of microglial processes with axonal segments, analyzing their associations with various axonal domains and how these interactions may differ between MS and TBI. Furthermore, we discuss potential functional consequences and molecular mechanisms of these interactions and how these may differ among various types of microglial-axonal interactions.

Keywords: Microglia; microglia-axonal interactions; multiple sclerosis; traumatic brain injury.

Figure 1.

Schematic representation of microglial process contacts in health and disease. Illustration demonstrating various microglial and monocytic contacts onto axonal segments. A: in the healthy brain, resident microglia (green) contact the neuronal cell body and axon initial segment. These microglia potentially express TNF-α and CSF1 and are involved in reduction of hyperexcitability in neurons. The dynamic surveying processes of non-activated ramified microglia also contact various areas of the axon in the healthy CNS. During development, contacts by resident microglia are involved in pre- and postsynaptic pruning; B: in MS, both resident microglia (green) and infiltrating peripheral monocytes (red) contact the nodes of Ranvier. Note that the processes of monocytes are found between the layers of myelin and the axon sheath, while the resident microglial processes are primarily in contact with adjacent monocytes and/or involved in debris clearance. Neuroinflammatory cells that have yet to be identified as either resident microglia or infiltrating monocytes (teal) that express TNF-α, INOS, Nox2, and higher levels of activated calpain, wrap the axon initial segment. This wrapping is involved in a notable reduction in the length of the axon initial segment; C: following TBI, macrophages (monocytes and/or microglia) phagocytosis the Wallerian debris from the degenerating distal axonal segments of an injured axons. Potential hyperexcitability of neurons following TBI induces microglial process convergence onto the neuronal soma via elevated ATP levels and/or glutamate levels. Rod microglia (green) are also common along the apical dendrite following injury; however, their function is currently unknown. Microglial process convergence onto the proximal injured axonal segment is associated with P2Y12 and potentially confers neuroprotective effects on the damaged axon leading to axonal sprouting. CNS: central nervous system; MS: multiple sclerosis; TBI: traumatic brain injury; TNF: tumor necrosis factor; CSF1: colony stimulating factor 1; INOS: inducible nitric oxide synthase; Nox2: NADPH oxidase 2

Figure 2.

Ultrastructure of microglial process contacts onto axonal segments following TBI. Electron micrographs of Iba-1 immuno-labeled microglia contacting: A: intact non-injured axons in sham-injured micro pig thalamus; B: injured axonal segment in the thalamus of micro pigs acutely (one day) following diffuse TBI. Iba-1-labeled microglial processes are pseudo-colored blue and the injured axon is pseudo-colored yellow for clarity. While few microglial processes were observed in direct contact with axons normally, microglial processes were observed in direct contact various segments of the neuron, including the soma (N = nucleus), AIS, and the proximal axonal swelling (X) of the injured neuron. Note that the proximal axonal segment of the injured neuron demonstrates ultrastructural characteristics of axonal sprouting (*). Scale bar: 5 μm. AIS: axon initial segment; TBI: traumatic brain injury