A microglia-cytokine axis to modulate synaptic connectivity and function

Abstract

Microglia have recently been recognized as key regulators of synapse development, function, and plasticity. Critical to progressing the field is the identification of molecular underpinnings necessary for microglia to carry out these important functions within neural circuits. Here, we focus a review specifically on roles for microglial cytokine signaling within developing and mature neural circuits. We review exciting new studies demonstrating essential roles for microglial cytokine signaling in axon outgrowth, synaptogenesis and synapse maturation during development, as well as synaptic transmission and plasticity in adulthood. Together, these studies identify microglia and cytokines as critical modulators of neural circuits within the healthy brain, with implications for a broad range of neurological disorders with disruptions in synaptic structure and function.

Figure1. CX3XR1-deficient mice have delayed synapse maturation and persistent defects in synaptic connectivity

(a) Top panel, during development in wild type animals, a subset of dendritic spines are pruned away (red spines) leaving the remaining subset to strengthen into mature neural circuits (green spines). In addition, there is a developmental shift from GluN2B (green) to GluN2A (blue)-containing postsynaptic NMDA receptors and an increase in AMPA/NMDA ratio. Middle panel, loss of CX3CR1 leads to a transient delay in spine pruning in the hippocampus and maturation of postsynaptic receptors in the hippocampus and barrel cortex. Bottom panel, once microglia density reaches wild type levels in the CX3CR1 deficient brain, spine density and postsynaptic receptor maturation are indistinguishable from wild type brains. (b) Adult animals deficient in CX3CR1 have decreased multi synapse boutons (MSBs) along the same dendrite in the hippocampus.

Figure 2. Microglial cytokine signaling regulates functional synapse plasticity

(a) Summary of microglial-derived TNFα effects on AMPA receptor (red) internalization within the nucleus accumbens following cocaine administration. (b) Summary CX3CL1 and IL-1β effects on LTP. Red receptors represent membrane-associated postsynaptic AMPA receptors necessary for LTP. Note the differing results assessing LTP in Cx3cr1^−/− (Maggi et al., 2009, top vs. Rogers et al., 2011, bottom).