Resting Microglia Directly Monitor the Functional State of SynapsesIn Vivoand Determine the Fate of Ischemic Terminals

Abstract

Recent studies have identified the important contribution of glial cells to the plasticity of neuronal circuits. Resting microglia, the primary immune effector cells in the brain, dynamically extend and retract their processes as if actively surveying the microenvironment. However, just what is being sampled by these resting microglial processes has not been demonstrated in vivo, and the nature and function of any interactions between microglia and neuronal circuits is incompletely understood. Using in vivo two-photon imaging of fluorescent-labeled neurons and microglia, we demonstrate that the resting microglial processes make brief (ϳ5 min) and direct contacts with neuronal synapses at a frequency of about once per hour. These contacts are activity-dependent, being reduced in frequency by reductions in neuronal activity. After transient cerebral ischemia, the duration of these microglia-synapse contacts are markedly prolonged (ϳ1 h) and are frequently followed by the disappearance of the presynaptic bouton. Our results demonstrate that at least part of the dynamic motility of resting microglial processes in vivo is directed toward synapses and propose that microglia vigilantly monitor and respond to the functional status of synapses. Furthermore, the striking finding that some synapses in the ischemic areas disappear after prolonged microglial contact suggests microglia contribute to the subsequent increased turnover of synaptic connections. Further understanding of the mechanisms involved in the microglial detection of the functional state of synapses, and of their role in remodeling neuronal circuits disrupted by ischemia, may lead to novel therapies for treating brain injury that target microglia.

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…A similar outcome was described in the sensorimotor cortex following immune activation; focal targeting of cortical microglia by stereotaxic delivery of heat-killed bacteria and subsequent peripheral bacterial challenge resulted in increased contact of Iba1 + and CD68 + microglia processes with neurons and decreased the number of presynaptic terminals compared with saline injections (Trapp et al, 2007). Increased elimination of dendritic spines is also observed under other conditions of injury that are characterized by microglial activation, including ischemia (Wake et al, 2009) and craniotomy (Xu et al, 2007). These results are consistent with the notion that microglia are sensitive to changes in the neuronal milieu and that certain molecular signals can promote pruning of synapses.…”

“…In support of this hypothesis, ultrastructural analysis in mice has revealed that microglial processes make direct contact not only with axon terminals and dendritic spines but also astrocytes and their perisynaptic processes that ensheath dendritic branches (Tremblay et al, 2010). Similarly, simultaneous in vivo two-photon imaging of fluorescently labeled neurons and microglia confirmed that microglial processes make frequent but brief contact with dendritic spines (Wake et al, 2009). These results put microglia in a prime position to monitor fluctuations in secreted elements at synapses, but it was unclear if their function could be altered by changes in neuronal activity.…”

“…These results put microglia in a prime position to monitor fluctuations in secreted elements at synapses, but it was unclear if their function could be altered by changes in neuronal activity. Remarkably, reducing basal neural activity in the visual cortex by either binocular occlusion or intraocular injection of tetrodotoxin (TTX) reduces the frequency that processes make contact with neurons (Wake et al, 2009). Similar results were obtained when animals were reared in complete darkness during a critical period of visual cortex development (Tremblay et al, 2010).…”

Neuroprotective roles of the P2Y2 receptor

“…Activation of microglia under pathological conditions results in their transformation to amoeboid morphology, migration toward the site of injury/damage, and release of neuroactive compounds that can have either neurotoxic or neuroprotective effects [171,172]. In vivo two-photon imaging revealed that resting microglia make brief but direct contacts with synapses without undergoing complete transformation/activation associated with a pathological phenotype [173,174]. In contrast, prolonged microglial cell contact with neurons can initiate a cascade of events that results in synaptic stripping and functional impairment of neuronal circuits [175,176].…”

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

“…It has been demonstrated that microglia can eliminate synaptic elements, neuronal precursors, and redundant newborn cells during adult neurogenesis (Sierra et al, 2010). Beside enabling synaptic pruning (Paolicelli et al, 2011), microglia modulate synaptic activity and plasticity (Moriguchi et al, 2003) and are fundamental in experience-mediated remodeling of neuronal circuits in diseased and healthy brain (Nimmerjahn et al, 2005;Wake et al, 2009;Rogers et al, 2011;Tremblay et al, 2010Tremblay et al, , 2012Schafer et al, 2012;Bechade et al, 2013;Sogn et al, 2013;Ji et al, 2013;Zhan et al, 2014).…”