Microglia: Activity-dependent regulators of neural circuits

Abstract

It has been more than a century since Pío del Río-Hortega first characterized microglia in histological stains of brain tissue. Since then, significant advances have been made in understanding the role of these resident central nervous system (CNS) macrophages. In particular, it is now known that microglia can sense neural activity and modulate neuronal circuits accordingly. We review the mechanisms by which microglia detect changes in neural activity to then modulate synapse numbers in the developing and mature CNS. This includes responses to both spontaneous and experience-driven neural activity. We further discuss activity-dependent mechanisms by which microglia regulate synaptic function and neural circuit excitability. Together, our discussion provides a comprehensive review of the activity-dependent functions of microglia within neural circuits in the healthy CNS, and highlights exciting new open questions related to understanding more fully microglia as key components and regulators of neural circuits.

Keywords: microglia; neural activity; synapses.

Figure 1.

Summary of activity-dependent microglia functions within neural circuits. A) Microglia can modulate synapse formation in response to a change in neuronal activity in response to neuron-derived molecules such as GABA and IL-33. GABA released by neurons binds GABA_B1R on microglia to regulate chandelier cell synaptogenesis. Likewise, neuron-derived, and possibly astrocyte-derived, IL-33 binds the microglia-expressed receptor IL1RL1/ST2 to induce microglia to phagocytose ECM to accommodate new synapses. Microglia have also been proposed to release more BDNF during heightened activity in the motor cortex to induce new synapse formation. B) Typically, a relative decrease in neuronal activity of a given synapse within a circuit triggers engulfment and elimination of that synaptic compartment by microglia (left panel). This microglia-mediated elimination of synapses involves multiple, different mechanisms that may act in concert, including modulation of surveillance and recruitment to synapses, transcriptional regulation of molecules regulating engulfment, and molecules that are critical to carry out engulfment of synaptic substrates; these mechanisms (listed) and can vary depending on the neuron subtype, brain region, and time of day. Microglia can also function to destabilize synapses in response to changes in neural activity (right panel). The most well characterized of these mechanisms is the interaction between neuron-expressed FN14 and TWEAK expressed on microglia, an interaction occurring in response to decreased activity in the visual system following dark rearing. C-D) In addition to modulating synapse structure, microglia can modulate the functional connectivity of neurons in response to neuronal activity. C)This has been most comprehensively shown in the context ATP (left) and cytokine-dependent modulation of synapses (right). Microglia can provide important feedback to block hyperexcitability by sensing ATP (left) released by hyperactive neurons and converting this ATP to adenosine via CD39 and CD73, which subsequently dampens activity. Microglia can also produce cytokines that modulate synaptic plasticity. D) TNFα in the context of synaptic scaling whereby in response to prolonged increases (left) or decreases (right) in activity, microglia-derived TNFα induces the scaling down (left) or up (right), respectively, of postsynaptic neurotransmitter receptors. IL-33, interleukin 33; IL1RL1 (or ST2), interleukin 1 receptor type 1; ECM, extracellular matrix; GABA, gamma-aminobutyric acid; GABA_B1R, GABA B1 receptor; BDNF, brain-derived neurotrophic factor; THIK-1, tandem pore domain halothane‐inhibited potassium channel 1; CX3CR1, fractalkine receptor; CX3CL1, fractalkine; ADAM10, a disintegrin and metalloproteinase domain-containing protein 10; ADRB2, beta-2 adrenergic receptor; A_2AR, adenosine A_2A receptor; CR3, complement receptor 3; PtdSer, phosphatidyl serine; CD47 =cluster of differentiation 47, SIRPα, signal regulatory protein alpha; TREM2, triggering receptor expressed on myeloid cells 2; GPR56, G-protein coupled receptor 56; MERTK, Mer tyrosine kinase; JAK2, janus kinase 2; STAT1, signal transducer and activator of transcription 1; BMAL1, brain and muscle ARNT-like protein 1; TWEAK, tumor necrosis factor-related weak inducer of apoptosis; FN14, fibroblast growth factor-inducible 14; ATP, adenosine triphosphate; CD39, cluster of differentiation 39; CD73, cluster of differentiation 73; TNFα, tumor necrosis factor alpha. Figure made with BioRender.

Figure 2.

Activity-dependent factors that influence microglial surveillance and recruitment to synapses. A) Microglia-expressed potassium channel THIK-1 regulates microglia motility and surveillance function, necessary for microglia to subsequently be recruited to and remodel synapses in response to activity. B) Changes in neural activity during monocular deprivation and hyperactivity can result in heightened ATP release from neurons, which has been suggested to then recruit microglia to synapses to modulate their structure and function. C) During hours of wakefulness, NA is higher in the cortex, resulting in decreased microglia–synapse contact through (ADRB2). In contrast, NA is lower during sleep resulting in enhanced microglia-synapse association. D) Microglia also respond to GABAergic neurotransmission through GABA_BR to modulate their contact with synapses and subsequently synapse remodeling. THIK-1, tandem pore domain halothane‐inhibited potassium channel 1; GABA, gamma-aminobutyric acid; GABA_BR, GABA B receptor; CX3CR1,fractalkine receptor; CX3CL1, fractalkine; ATP, adenosine triphosphate; NA, noradrenaline/norepinephrine; ADRB2, beta-2 adrenergic receptor. Figure made with BioRender.

Figure 3.

Putative mechanisms by which microglia engulf and remove synaptic material in response to changes in neural activity. A) Microglia-mediated phagocytosis of an intact synaptic membrane. B) Synapses degenerate and leave behind synaptic debris, which is then phagocytosed by microglia. C) Microglia engulf synaptic membranes (trogocytosis), ultimately leading to synapse removal. Figure made with BioRender.