Synaptic dysfunction is a hallmark of many neurodegenerative and psychiatric brain disorders, yet we know little about the mechanisms that underlie synaptic vulnerability. Although neuroinflammation ...and reactive gliosis are prominent in virtually every CNS disease, glia are largely viewed as passive responders to neuronal damage rather than drivers of synaptic dysfunction. This perspective is changing with the growing realization that glia actively signal with neurons and influence synaptic development, transmission and plasticity through an array of secreted and contact-dependent signals. We propose that disruptions in neuron-glia signaling contribute to synaptic and cognitive impairment in disease. Illuminating the mechanisms by which glia influence synapse function may lead to the development of new therapies and biomarkers for synaptic dysfunction.
Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain ...unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs.
•“Don’t eat me” signals are developmentally regulated in the dLGN during peak pruning•CD47KO and SIRPαKO mice exhibit increased microglial engulfment•CD47KOs show increased functional pruning and sustained reductions in synapse number•CD47 is localized to more active inputs and required for activity-dependent engulfment
Lehrman et al. discover that CD47-SIRPα signaling prevents excess microglial phagocytosis during developmental synaptic pruning. They find that CD47 is required for neuronal activity-mediated changes in microglial engulfment and that mice lacking CD47 display increased structural and functional pruning.
C1q, the initiator of the classical complement cascade, mediates synapse elimination in the postnatal mouse dorsolateral geniculate nucleus of the thalamus and sensorimotor cortex. Here, we asked ...whether C1q plays a role in experience-dependent synaptic refinement in the visual system at later stages of development. The binocular zone of primary visual cortex (V1b) undergoes spine loss and changes in neuronal responsiveness following the closure of one eye during a defined critical period a process referred to as ocular dominance plasticity (ODP). We therefore hypothesized that ODP would be impaired in the absence of C1q, and that V1b development would also be abnormal without C1q-mediated synapse elimination. However, when we examined several features of V1b development in mice lacking C1q, we found that the densities of most spine populations on basal and proximal apical dendrites, as well as firing rates and ocular dominance, were normal. C1q was only transiently required for the development of spines on apical, but not basal, secondary dendrites. Dendritic morphologies were also unaffected. Although we did not observe the previously described spine loss during ODP in either genotype, our results reveal that the animals lacking C1q had normal shifts in neuronal responsiveness following eye closure. Experiments were performed in both male and female mice. These results suggest that the development and plasticity of the mouse V1b is grossly normal in the absence of C1q.
These findings illustrate that the development and experience-dependent plasticity of V1b is mostly normal in the absence of C1q, even though C1q has previously been shown to be required for developmental synapse elimination in the mouse visual thalamus as well as sensorimotor cortex. The V1b phenotypes in mice lacking C1q are more similar to the mild defects previously observed in the hippocampus of these mice, emphasizing that the contribution of C1q to synapse elimination appears to be dependent on context.
During inflammation, Ly6C
monocytes are rapidly mobilized from the bone marrow (BM) and are recruited into inflamed tissues, where they undergo monocyte-to-phagocyte transition (MTPT). The in vivo ...developmental trajectories of the MTPT and the contribution of individual cytokines to this process remain unclear. Here, we used a murine model of neuroinflammation to investigate how granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFNγ), two type 1 cytokines, controlled MTPT. Using genetic fate mapping, gene targeting and high-dimensional single-cell multiomics analyses, we found that IFNγ was essential for the gradual acquisition of a mature inflammatory phagocyte phenotype in Ly6C
monocytes, while GM-CSF was required to license interleukin-1β (IL-1β) production, phagocytosis and oxidative burst. These results suggest that the proinflammatory cytokine environment guided MTPT trajectories in the inflamed central nervous system (CNS) and indicated that GM-CSF was the most prominent target for the disarming of monocyte progenies during neuroinflammation.
Brief monocular deprivation (MD) shifts ocular dominance and reduces the density of thalamic synapses in layer 4 of the mouse primary visual cortex (V1). We found that microglial lysosome content is ...also increased as a result of MD. Previous studies have shown that the microglial fractalkine receptor CX3CR1 is involved in synaptic development and hippocampal plasticity. We therefore tested the hypothesis that neuron-to-microglial communication via CX3CR1 is an essential component of visual cortical development and plasticity in male mice. Our data show that CX3CR1 is not required for normal development of V1 responses to visual stimulation, multiple forms of experience-dependent plasticity, or the synapse loss that accompanies MD in layer 4. By ruling out an essential role for fractalkine signaling, our study narrows the search for understanding how microglia respond to active synapse modification in the visual cortex.
Microglia in the visual cortex respond to monocular deprivation with increased lysosome content, but signaling through the fractalkine receptor CX3CR1 is not an essential component in the mechanisms of visual cortical development or experience-dependent synaptic plasticity.
Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood-brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the ...control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (
), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in
mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti-ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of
mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in
;
mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.
In the central nervous system (CNS), myelin formation and repair are regulated by oligodendrocyte (OL) lineage cells, which sense and integrate signals from their environment, including from other ...glial cells and the extracellular matrix (ECM). The signaling pathways that coordinate this complex communication, however, remain poorly understood. The adhesion G protein-coupled receptor ADGRG1 (also known as GPR56) is an evolutionarily conserved regulator of OL development in humans, mice, and zebrafish, although its activating ligand for OL lineage cells is unknown. Here, we report that microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OL precursor cells (OPCs) in the presence of the ECM protein laminin and that TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation. Signaling by TG2/laminin to ADGRG1 on OPCs additionally improves remyelination in two murine models of demyelination. These findings identify a novel glia-to-glia signaling pathway that promotes myelin formation and repair, and suggest new strategies to enhance remyelination.
Changes in excitatory neuron and synapse structure have been recognized as a potential physical source of age-related cognitive decline. Despite the importance of inhibition to brain plasticity, ...little is known regarding aging-associated changes to inhibitory neurons. Here we test for age-related cellular and circuit changes to inhibitory neurons of mouse visual cortex. We find no substantial difference in inhibitory neuron number, inhibitory neuronal subtypes, or synapse numbers within the cerebral cortex of aged mice compared with younger adults. However, when comparing cortical interneuron morphological parameters, we find differences in complexity, suggesting that arbors are simplified in aged mice.
two-photon microscopy has previously shown that in contrast to pyramidal neurons, inhibitory interneurons retain a capacity for dendritic remodeling in the adult. We find that this capacity diminishes with age and is accompanied by a shift in dynamics from balanced branch additions and retractions to progressive prevalence of retractions, culminating in a dendritic arbor that is both simpler and more stable. Recording of visually evoked potentials shows that aging-related interneuron dendritic arbor simplification and reduced dynamics go hand in hand with loss of induced stimulus-selective response potentiation (SRP), a paradigm for adult visual cortical plasticity. Chronic treatment with the antidepressant fluoxetine reversed deficits in interneuron structural dynamics and restored SRP in aged animals. Our results support a structural basis for age-related impairments in sensory perception, and suggest that declines in inhibitory neuron structural plasticity during aging contribute to reduced functional plasticity.
Structural alterations in neuronal morphology and synaptic connections have been proposed as a potential physical basis for age-related decline in cognitive function. Little is known regarding aging-associated changes to inhibitory neurons, despite the importance of inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps. Here we show that brain aging goes hand in hand with progressive structural simplification and reduced plasticity of inhibitory neurons, and a parallel decline in sensory map plasticity. Fluoxetine treatment can attenuate the concurrent age-related declines in interneuron structural and functional plasticity, suggesting it could provide an important therapeutic approach for mitigating sensory and cognitive deficits associated with aging.
Macrophages are involved in immune defense, organogenesis and tissue homeostasis. Macrophages contribute to the different phases of mammary gland remodeling during development, pregnancy and ...involution postlactation. Less is known about the dynamics of mammary gland macrophages in the lactation stage. Here, we describe a macrophage population present during lactation in mice. By multiparameter flow cytometry and single-cell RNA sequencing, we identified a lactation-induced CD11c
CX3CR1
Dectin-1
macrophage population (liMac) that was distinct from the two resident F4/80
and F4/80
macrophage subsets present pregestationally. LiMacs were predominantly monocyte-derived and expanded by proliferation in situ concomitant with nursing. LiMacs developed independently of IL-34, but required CSF-1 signaling and were partly microbiota-dependent. Locally, they resided adjacent to the basal cells of the alveoli and extravasated into the milk. We found several macrophage subsets in human milk that resembled liMacs. Collectively, these findings reveal the emergence of unique macrophages in the mammary gland and milk during lactation.
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