Microglia, the resident immune cells of the brain, perform elaborate surveillance where they physically interact with neuronal elements. A novel form of microglia-neuron interaction named microglial process convergence (MPC) toward neuronal axons and dendrites have recently been described. However, the molecular regulators and pathological relevance of MPCs have not been explored. Here, using high resolution two-photon imaging in vivo and ex vivo, we observed a dramatic increase in MPCs following kainic acid- or pilocarpine-induced experimental seizures that was reconstituted following glutamate treatment in slices from mice. Interestingly, a deficiency of the fractalkine receptor (CX3CR1) decreased MPCs while fractalkine (CX3CL1) treatment increased MPCs, suggesting that fractalkine signaling is a critical regulator of these microglia-neuron interactions. Furthermore, we found that IL-1β was necessary and sufficient to trigger CX3CR1-dependent MPCs. Finally, we show that a deficiency in fractalkine signaling corresponded with increased seizure phenotypes. Together, our results identify the neuroglial CX3CL1-CX3CR1 communication axis as a modulator of potentially neuroprotective microglia-neuron physical interactions during conditions of neuronal hyperactivity.
Significance Statement Microglia, the immune cells of the brain, are exquisitely sensitive to disturbances in brain homeostasis and are critical for proper neuronal function. Seizures are a common disorder of the brain. However, the dynamics of microglial interactions with neurons following such conditions are not known. Using high resolution real time imaging in living mouse brain tissues, we have discovered an interesting phenomenon whereby brain microglia physically interact with neurons following hyperactive conditions. Specifically, we have elucidated relevant mechanisms and molecular signaling cascade governing these interactions. In addition, our findings suggest neuroprotective roles for microglial interaction with neurons. Together, our results suggest that enhancing microglial function during seizures may serve beneficial therapeutic functions.
Authors report no conflict of interest.
HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) [R01NS088627] ; HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) .