There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of ...disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.
Neuron-Glia Signaling in Synapse Elimination Wilton, Daniel K; Dissing-Olesen, Lasse; Stevens, Beth
Annual review of neuroscience,
07/2019, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Maturation of neuronal circuits requires selective elimination of synaptic connections. Although neuron-intrinsic mechanisms are important in this process, it is increasingly recognized that glial ...cells also play a critical role. Without proper functioning of these cells, the number, morphology, and function of synaptic contacts are profoundly altered, resulting in abnormal connectivity and behavioral abnormalities. In addition to their role in synaptic refinement, glial cells have also been implicated in pathological synapse loss and dysfunction following injury or nervous system degeneration in adults. Although mechanisms regulating glia-mediated synaptic elimination are still being uncovered, it is clear this complex process involves many cues that promote and inhibit the removal of specific synaptic connections. Gaining a greater understanding of these signals and the contribution of different cell types will not only provide insight into this critical biological event but also be instrumental in advancing knowledge of brain development and neural disease.
An explosion of findings driven by powerful new technologies has expanded our understanding of microglia, the resident immune cells of the central nervous system (CNS). This wave of discoveries has ...fueled a growing interest in the roles that these cells play in the development of the CNS and in the neuropathology of a diverse array of disorders. In this review, we discuss the crucial roles that microglia play in shaping the brain-from their influence on neurons and glia within the developing CNS to their roles in synaptic maturation and brain wiring-as well as some of the obstacles to overcome when assessing their contributions to normal brain development. Furthermore, we examine how normal developmental functions of microglia are perturbed or remerge in neurodevelopmental and neurodegenerative disease.
Abstract The role of microglia in healthy brains is just beginning to receive notice. Recent studies have revealed that these phagocytic cells control the patterning and wiring of the developing ...central nervous system (CNS) by regulating, amongst many other processes, programmed cell death, activity-dependent synaptic pruning and synapse maturation. Microglia also play important roles in the mature brain and have demonstrated effects on behavior. Converging evidence from human and mouse studies together raise questions as to the role of microglia in disorders of brain development such as autism and, schizophrenia. In this review, we summarize a number of major findings regarding the role of microglia in brain development and highlight some key questions and avenues for future study. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.
Neuronal communication underlies all brain activity and the genesis of complex behavior. Emerging research has revealed an unexpected role for immune molecules in the development and plasticity of ...neuronal synapses. Moreover microglia, the resident immune cells of the brain, express and secrete immune-related signaling molecules that alter synaptic transmission and plasticity in the absence of inflammation. When inflammation does occur, microglia modify synaptic connections and synaptic plasticity required for learning and memory. Here we review recent findings demonstrating how the dynamic interactions between neurons and microglia shape the circuitry of the nervous system in the healthy brain and how altered neuron–microglia signaling could contribute to disease.
Microglia–astrocyte interactions represent a delicate balance affecting neural cell functions in health and disease. Tightly controlled to maintain homeostasis during physiological conditions, rapid ...and prolonged departures during disease, infection, and following trauma drive multiple outcomes: both beneficial and detrimental. Recent sequencing studies at the bulk and single-cell level in humans and rodents provide new insight into microglia–astrocyte communication in homeostasis and disease. However, the complex changing ways these two cell types functionally interact has been a barrier to understanding disease initiation, progression, and disease mechanisms. Single cell sequencing is providing new insights; however, many questions remain. Here, we discuss how to bridge transcriptional states to specific functions so we can develop therapies to mediate negative effects of altered microglia–astrocyte interactions.
Microglia are resident immune cells of the brain, which derive from a different cell lineage to all other cells in the brain. They are highly motile cells, constantly patrolling the brain parenchyma.Astrocytes are the largest cell component of the brain and develop from a common progenitor along with neurons and oligodendrocytes. They tile the entire brain and do not migrate during normal physiology. These two cell types are important for normal mammalian brain development and respond rapidly to disease, infection, and trauma.Microglia and astrocytes interact via contact-dependent and secreted factors to modulate their function during normal health and in disease. Microglia can drive reactivity in astrocytes via the release of specific cytokines, while astrocytes can drive dysfunction in microglia by withholding cholesterol.Many tools exist to manipulate both microglia and astrocytes, however, complete removal of astrocytes is currently impossible as this results in death.scRNASeq experiments must be both adequately powered and take into account possible artifacts as a result of subsampling when disseminating results. Ideally, cluster-specific differentially expressed genes should be validated using visualization methods (in situ hybridization or spatial transcriptomic approaches) and functional assays.Caution should be taken in the nomenclature of different ‘activation’ states of both microglia and astrocytes. While no method is perfect, the field needs to clearly state what constitutes a subset of cells: biologically relevant and functionally characterized descriptions will be the most beneficial.
Emerging evidence indicates that signaling between perisynaptic astrocytes and neurons at the tripartite synapse plays an important role during the critical period when neural circuits are formed and ...refined. Cross-talk between astrocytes and neurons during development mediates synaptogenesis, synapse elimination and structural plasticity through a variety of secreted and contact-dependent signals. Recent live imaging studies reveal a dynamic and cooperative interplay between astrocytes and neurons at synapses that is guided by a variety of molecular cues. A unifying theme from these recent findings is that astrocytes can promote the development and plasticity of synaptic circuits. Insight into the molecular mechanisms by which astrocytes regulate the wiring of the brain during development could lead to new therapeutic strategies to promote repair and rewiring of neural circuits in the mature brain following CNS injury and neurodegenerative disease.
Glial cells play critical roles in the normal development and function of neural circuits, but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of ...brain pathology. In Huntington's disease (HD), glial cells both lose normal functions and gain neuropathic phenotypes. In addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression in specific glial cell types is sufficient to induce both pathology and Huntington's disease–related impairments in motor and cognitive performance, suggesting that these cells may drive the development of certain aspects of Huntington's disease pathogenesis. In support of this imaging studies in pre-symptomatic HD patients and work on mouse models have suggested that glial cell dysfunction occurs at a very early stage of the disease, prior to the onset of motor and cognitive deficits. Furthermore, selectively ablating mHTT from specific glial cells or correcting for HD-induced changes in their transcriptional profile rescues some HD-related phenotypes, demonstrating the potential of targeting these cells for therapeutic intervention. Here we review emerging research focused on understanding the involvement of different glial cell types in specific aspects of HD pathogenesis. This work is providing new insight into how HD impacts biological functions of glial cells in the healthy brain as well as how HD induced dysfunction in these cells might change the way they integrate into biological circuits.
An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS ...synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression.
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