A microglia-cytokine axis to modulate synaptic connectivity and function
Graphical abstract
Introduction
Nearly 100 years ago, Pío del Río-Hortega stained fixed tissue with silver carbonate to reveal mysterious brain cells that he called ‘microglia’ [1]. From this simple tissue preparation, he made the keen observation that these resident brain macrophages were uniquely dynamic with robust ‘plasticity of their protoplasm’ and a high degree of physical interaction with other nervous system cells. Fast forward to the 21st century, del Río-Hortega's suspicions are being realized with exciting work defining key functional roles for microglia within neural circuits in the healthy brain.
Some of the first evidence that suggested microglia were playing important functions within the healthy brain were seminal 2-photon live imaging studies in mice, demonstrating that microglial processes in the intact healthy brain were highly dynamic and continuously surveying their extracellular environment [2, 3]. This surveillance activity was later shown to be highly sensitive to neural activity whereby microglia modulated the motility of their processes in response to changes in neural activity and sensory experience [4, 5, 6, 7, 8, 9]. Further live and static imaging revealed remarkable activity-dependent physical interactions and contact between microglial processes and synaptic elements (dendritic spines and presynaptic boutons) under steady-state conditions [4, 5, 10]. Indeed, given an estimated 94% of microglial processes are in contact with synaptic elements at any given point in time [4], this begs the question--what is the function(s) of microglia at synapses? It is now increasingly clear that microglia-derived molecules regulate synaptic connectivity including regulation of axon outgrowth, synaptogenesis, synapse maturation, synaptic pruning, basal synaptic transmission, and functional synapse plasticity [11]. Here, we review exciting new work on emerging roles for microglial cytokine signaling necessary for modulating synaptic connectivity and function.
Section snippets
Cytokines: An introduction
Cytokines are an exceptionally large and diverse group of small signaling proteins that, upon binding to their cognate receptors, activate cellular pathways to modulate a large variety of physiological and pathological processes [12]. Based on their structural homology, cytokines are subdivided in different classes: chemokines, lymphokines, tumor necrosis factors (TNFs), colony stimulating factors (CSFs), interferons (IFNs) and interleukins (ILs). These classes are further divided into
Microglial cytokine signaling: establishing synaptic connectivity
Prior to forming synapses, newborn axons must grow toward their eventual synaptic targets. Recent work in the embryonic brain has suggested a key role for microglia and microglial cytokine signaling in regulating initial axon outgrowth. When microglia were absent in the embryonic brain by genetic targeting the transcription factor PU.1 or pharmacological blockade of the cytokine colony stimulating factor 1 receptor (CSF1R), a trophic factor necessary for microglial survival, there was exuberant
Microglial cytokine signaling: synapse maturation
During development, synaptic connections first form in excess to establish immature neural circuits. These nascent circuits then undergo synaptic pruning in which less active synapses are eliminated. The remaining synapses in the circuit are then functionally strengthened and elaborated into mature neural circuits. Some of the first evidence suggesting microglia play roles in these maturation processes was work demonstrating that microglia engulf and prune away less active synapses during brain
Microglial-derived cytokine signaling: regulating synaptic transmission and functional plasticity
Microglia are in close apposition to and physically interact with synapses, dynamically sense changes in neural activity, and express several molecules known to modulate synaptic transmission [22]. Likewise, there has been a large amount of literature demonstrating that cytokines affect a large array of synaptic properties and physiology [23]. Much of this work has suggested that cytokine signaling from other cell types such as neurons and astrocytes directly affects synapses, although it is
Conclusions
Microglia are now emerging as key regulators of structural and functional synapses in the healthy brain. Among the molecular pathways identified, cytokines and cytokine receptors have emerged as important regulators of microglia function at synapses. During embryogenesis, microglial CX3CR1 signaling has been identified as regulator of axon outgrowth. Microglial IL-10 has been suggested to promote synaptogenesis in vitro. During postnatal development, microglial CX3CR1 signaling regulates
Funding Sources
This work was supported by the National Institutes of Health (NIMH R00MH102351; DS, NIMH R01MH113743; DS, NIGMS T32GM107000; PF); The Charles H. Hood Foundation (DS); The Brain and Behavior Research Foundation (DS); The Worcester Foundation (DS); the German Research Foundation (DFG; WE 6170/1-1; SW).
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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