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Glial cells – traditionally thought as simply the “glue” of the nervous system – are increasingly recognized to play a critical role in the development and function of the brain. Importantly, glial cell dysfunction has recently been shown to contribute to various neurological disorders, such as autism, schizophrenia, pain, and neurodegeneration. Understanding the function of glial cells under normal, physiological conditions, as well as how it goes awry in disease, has the potential to revolutionize how we think about the function and dysfunction of the nervous system, and inspire the development of new therapies to treat these devastating disorders.
A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
Microglia are the macrophages of the CNS, with innate neuroimmune function, and play important roles in tissue homeostasis, CNS development and neurodegeneration. Here human microglial gene expression profiles were generated. Human and mouse microglia were highly similar, except for aging-regulated genes, indicating that microglial aging differs between humans and mice.
Microglia are CNS-resident macrophages, but studying their functions in health and disease has been challenging due to a lack of specific markers. Greter and colleagues identify the transcription factor Sall1 as being uniquely associated with microglia in the CNS, where it is important for defining their fate and homeostatic function.
μ opioid receptors (MORs) expressed on primary afferent nociceptor neurons are responsible for two maladaptive side-effects of chronic opioid use: opioid tolerance and opioid-induced hyperalgesia (pain). A combination therapy of opioid receptor agonism plus peripheral-restricted MOR antagonism abrogates these side-effects while preserving opioid analgesia in rodent models of peri-operative and chronic pain.
The contribution of glia to Huntington's disease is unclear. The authors show that human glial progenitor cells (GPCs) expressing mutant huntingtin impair motor performance when engrafted into wild type mice, and wild type human GPCs ameliorate disease phenotypes when engrafted into an HD mouse model.
Calcium signalling in astrocytes, driven through the octopamine/tyramine receptor and the TRP channel Water witch, is essential for neuromodulation and sensory responses in Drosophila larvae.
In a mouse model of ischaemia, mitochondrial particles released from astroctyes are taken up by adjacent neurons, leading to enhanced cell survival signalling; disruption of this release mechanism resulted in worsened neurological outcomes.
Neurotrophic factors produced by enteric glia in response to microbiota and alarmin cues regulate IL-22 production by group 3 innate lymphoid cells in the gut; disruption of this pathway leads to impaired clearance of Citrobacter rodentium and defects in epithelial integrity in a model of intestinal inflammation.
A heterotypic cell interaction between astrocytes and tumour cells colonizing the brain is discovered; by establishing gap junctions, tumour cells trigger the activation of innate immune response signalling in astrocytes, which results in the secretion of factors that support growth and chemoresistance in brain metastatic cells.
Mouse models of Alzheimer’s disease show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline; driving neurons to oscillate at gamma frequency (40 Hz) reduces levels of amyloid-β peptides.
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People infected with West Nile virus often experience cognitive side effects including memory loss through unknown mechanisms; mice and humans infected with the virus experience a loss in hippocampal presynaptic terminals, which can be reversed by disrupting complement or microglia in mice.
Microglial phagocytosis is required for neurogenic niche maintenance and response to injury; the TAM kinases Mer and Axl are expressed by microglia in the adult CNS, and mediate the clearance of apoptotic cells from the niche.
Sustained delivery of axon-specific growth factors not typically present in spinal cord lesions allows for robust axonal regrowth only if the astrocytic scar is present—a result that questions the prevailing dogma and suggests that astrocytic scarring aids rather than prevents central nervous system axon regeneration post injury.
The acquisition of a new skill or motor program is thought to be mediated by changes in neuronal plasticity at early stages of learning, which is later stabilized by new myelin generated by oligodendrocytes. In this study, the authors show that oligodendrocyte precursors exist in a ‘primed’ state, which allows them to contribute to early stages of motor learning.
The nature of astrocyte diversity in the adult brain has remained poorly defined. The authors identify five astrocyte subpopulations in the brain that exhibit extensive molecular and functional diversity. They uncover correlative populations in malignant glioma, providing insight into how diverse astrocyte populations contribute to synaptogenesis, tumor pathophysiology and neurological disease.
Neocortical resident microglia are long-lived cells. Füger et al. report that approximately half of these cells survive for the entire lifespan of a mouse. While microglial proliferation under homeostatic conditions is low, proliferation is increased in a mouse model of Alzheimer's disease.
Microglia are the tissue-resident macrophages of the brain. Ouyang and colleagues show the ER-resident transmembrane protein NRROS is necessary for proper development and function of microglia. Mice lacking NRROS exhibit neurologic defects and die prematurely.
Gliomas recruit and manipulate microglial function to promote their growth. Joseph and colleagues reveal the molecular basis of this manipulation by showing that gliomas trigger S-nitrosylation of microglial caspase-3 and thereby initiate a tumor-promoting phenotype.
Microglia progenitors seed the central nervous system from the yolk sac, but little is known about the origin of non-parenchymal macrophages. Prinz and colleagues demonstrate that these macrophages in the central nervous system are related to but distinct from microglia and are largely of embryonic origin.
The release of ATP from spinal microglia via pannexin-1 channels is required for withdrawal symptoms after termination of chronic opioid treatment in rodents, and pharmacological blockade of pannexin-1 channels reduces the severity of withdrawal without affecting opiate analgesia.
After upregulation of AHR in astrocytes by type I interferons, commensal-microbe-derived metabolites of dietary tryptophan act on astrocytes to suppress CNS inflammation.
In response to signals from afferent TRPV1+ C-fibers, STAT3-dependent upregulation of LCN2 in reactive astrocytes of the spinal dorsal horn amplifies itch signaling in multiple rodent models of atopic and contact dermatitis.
In a mouse model of spinal cord injury, reactive astrogliosis is found to be context dependent and reversible. Blockade of type I collagen–reactive astrocyte interactions prevents astrocyte scar formation and facilitates functional recovery after injury.
How microglia contribute to brain injury or repair is unclear. Here combining microglia manipulations and calcium imaging, the authors show that selective elimination of microglia leads to disrupted neuronal calcium dynamics and markedly increased brain injury after cerebral ischemia.
Core clock genes, such asBmal1, are expressed in astrocytes, but their contribution to the timekeeping system is unknown. Barca-Mayo et al. report that deletion of Bmal1in Glast+ astrocytes alters the neuronal clock through GABA signalling, leading to abnormal circadian locomotor behaviour and impaired cognition in mice.
While transcranical direct current stimulation (tDCS) is used in clinical setting, its cellular mechanism of action is unclear. Here, Hajime Hirase and colleagues visualize cellular response in mouse brain to tDCS and show robust astrocyte activation that coincide with plasticity changes.
Microglia and monocytes contribute to neuropathic pain states, but the precise role of the two cell types is not clear. Here Peng et al.use temporally controlled ablation of monocytes and microglia in mice to show that these cells work together to initiate neuropathic-pain like behaviour, but are less important in the maintenance phase.
How neurons and neuronal activity regulate astrocyte functions is poorly understood. Haselet al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.
Glial scars are thought to provide a biochemical and mechanical barrier to neuronal regeneration post-injury, but the mechanical properties of the scars have not been studied in detail. Here the authors perform atomic force microscopy measurements of glial scars from the injured rat cortex and spinal cord, and find that brain tissue softens in response to the injury.
Hidden hearing loss (HHL) is an auditory neuropathy that impairs one’s ability to hear, particularly in a noisy environment. Here the authors show that in mice, transient loss of cochlear Schwann cells results in permanent disruption of the cochlear heminodal structure, leading to auditory deficits characteristic of HHL.