The microglial fractalkine receptor is not required for activity-dependent plasticity in the mouse visual system

Abstract

Microglia have recently been implicated as key regulators of activity-dependent plasticity, where they contribute to the removal of inappropriate or excess synapses. However, the molecular mechanisms that mediate this microglial function are still not well understood. Although multiple studies have implicated fractalkine signaling as a mediator of microglia-neuron communications during synaptic plasticity, it is unclear whether this is a universal signaling mechanism or whether its role is limited to specific brain regions and stages of the lifespan. Here, we examined whether fractalkine signaling mediates microglial contributions to activity-dependent plasticity in the developing and adolescent visual system. Using genetic ablation of fractalkine’s cognate receptor, CX3CR1, and both ex vivo characterization and in vivo imaging in mice, we examined whether fractalkine signaling is required for microglial dynamics and modulation of synapses, as well as activity-dependent plasticity in the visual system. We did not find a role for fractalkine signaling in mediating microglial properties during visual plasticity. Ablation of CX3CR1 had no effect on microglial density, distribution, morphology, or motility, in either adolescent or young adult mice across brain regions that include the visual cortex. Ablation of CX3CR1 also had no effect on baseline synaptic turnover or contact dynamics between microglia and neurons. Finally, we found that fractalkine signaling is not required for either early or late forms of activity-dependent visual system plasticity. These findings suggest that fractalkine is not a universal regulator of synaptic plasticity, but rather has heterogeneous roles in specific brain regions and life stages.

Cerebellar microglia are dynamically unique and survey Purkinje neurons in vivo

“…We also demonstrated that microglial processes interact dynamically with both the dendrites and somas of Purkinje neurons in the Cb, similarly to their cortical counterparts (Wake et al, ; Tremblay et al, ). These interactions were highly variable in duration, which agrees with previous findings in cortex from our lab (Tremblay et al, ; Lowery et al, ). Our findings suggest that cerebellar microglia may have unique morphological and dynamic behaviors that support different roles that these microglia play in cerebellar function as compared to microglia in other parts of the brain.…”

“…The lower density of microglia in both the ML and PCL would make it harder for microglia to interact with a large number of synapses, possibly limiting their roles in plasticity or increasing the delay between activity‐driven synaptic changes and microglial recruitment. While the duration of contacts between microglia and neurons is highly variable in the Cb and similar to what has been reported in cortex, it is difficult to directly compare such contacts quantitatively in brain areas where the neuronal architecture is different (Wake et al, ; Tremblay et al, ; Lowery et al, ). However, close apposition of microglial processes and neuronal dendrites over distance (e.g., extending along a dendrite) is rarely seen in the cortex, suggesting that the mode of contact may be fundamentally different in the two brain areas.…”

“…While the duration of contacts between microglia and neurons is highly variable in the Cb and similar to what has been reported in cortex, it is difficult to directly compare such contacts quantitatively in brain areas where the neuronal architecture is different (Wake et al, 2009;Tremblay et al, 2010;Lowery et al, 2017). However, close apposition of microglial processes and neuronal dendrites over distance (e.g., extending along a dendrite) is rarely seen in the cortex, suggesting that the mode of contact may be fundamentally different in the two brain areas.…”

“…We believe that this study is the first to pair fixed tissue analysis with in vivo imaging of cerebellar microglia and provide insight into the dynamic behavior of these cells within their native milieu. To image microglia in vivo , we used a mouse lacking one copy of CX3CR1, an important receptor for many microglial functions (Maggi et al, ; Hoshiko et al, ; Arnoux et al, ; Paolicelli et al, ; Lowery et al, ; Schecter et al, ). While this has to be taken into account, many of our results agree with previous studies carried out in wild type animals.…”

A microglia-cytokine axis to modulate synaptic connectivity and function

“…In contrast to the studies described above, a very recent study provided in vivo evidence that CX3CR1-deficient microglia within the visual cortex had an amplified response to laser-induced injury while basal microglial dynamics and interactions with synapses were unaltered [65•]. They also provide data that Cx3cr1 −/− mice have normal activity-dependent plasticity within the visual cortex.…”