Microglia-neuron communication at nodes of Ranvier depends on neuronal activity through potassium release and contributes to myelin repair

Abstract

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct and stable site of interaction between microglia and axons, in both mouse and human tissue. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglianode interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Disrupting axonal K+ flux following demyelination polarizes microglia towards a pro-inflammatory phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron communication, participating in the pro-remyelinating effect of microglia after myelin injury.

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination

“…We describe a "nodal-glial" interface that appears necessary for long-term neuron-OL K + shuttling and homeostasis during inflammatory demyelination and demonstrate the importance for nodal-glial interaction during health and disease, similar to previous work on neuron-microglia crosstalk (56). This spatial and functional interface comprises outward rectifying Kv7 (41) and inward-rectifying OL-Kir4.1 K + channels at the NoR and the AIS (49).…”

Neuron–Oligodendrocyte Communication in Myelination of Cortical GABAergic Cells

“…Astrocyte processes may participate in potassium buffering at the nodal gap [ 136 , 137 ]. Recent work shows microglial cells preferentially contact axons at nodes of Ranvier, and contact probability is enhanced by K + released at the nodes by neuronal activity [ 138 ]. Oligodendrocyte precursor cells also contact nodes of Ranvier, but their role remains elusive [ 137 ].…”

Microglia‐dependent remodeling of neuronal circuits

“…Together these studies demonstrated that microglia dynamics is affected by the binding of neurotransmitters to neuronal ionotropic receptors, suggesting that the signaling is indirect and activity-driven, while microglia per se can directly respond to certain neuromodulators, such as purines. Additionally, the activity of microglial THIK-1 has been shown to function as a potassium sensor when in close proximity to both axons and synapses and may function as a readout for neuronal membrane activity (Madry et al, 2018;Ronzano et al, 2021). Indeed, abrogation or inhibition of THIK-1 leads to an increase in synaptic density because of defective microglia pruning (Izquierdo et al, 2021).…”