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Concept: Glial cells


Neuron-microglia co-cultures treated with pro-inflammatory agents are a useful tool to study neuroinflammation in vitro, where to test the potential neuroprotective effect of anti-inflammatory compounds. However, a great diversity of experimental conditions can be found in the literature, making difficult to select the working conditions when considering this approach for the first time. We compared the use of neuron-primary microglia and neuron-BV2 cells (a microglial cell line) co-cultures, using different neuron:microglia ratios, treatments and time post-treatment to induce glial activation and derived neurotoxicity. We show that each model requires different experimental conditions, but that both neuron-BV2 and neuron-primary microglia LPS/IFN-γ-treated co-cultures are good to study the potential neuroprotective effect of anti-inflammatory agents. The contribution of different pro-inflammatory parameters in the neurotoxicity induced by reactive microglial cells was determined. IL-10 pre-treatment completely inhibited LPS/IFN-γ-induced TNF-α and IL-6 release, and COX-2 expression both in BV2 and primary microglial cultures, but not NO production and iNOS expression. However, LPS/IFN-γ induced neurotoxicity was not inhibited in IL-10 pre-treated co-cultures. The inhibition of NO production using the specific iNOS inhibitor 1400 W totally abolished the neurotoxic effect of LPS/IFN-γ, suggesting a major role for NO in the neurotoxic effect of activated microglia. Consequently, among the anti-inflammatory agents, special attention should be paid to compounds that inhibit NO production.

Concepts: Enzyme inhibitor, Inhibitor, Glial cell, Glial cells, Microglia


Although retinal neurodegenerative conditions such as age-related macular degeneration, glaucoma, diabetic retinopathy, retinitis pigmentosa, and retinal detachment have different etiologies and pathological characteristics, they also have many responses in common at the cellular level, including neural and glial remodeling. Structural changes in Müller cells, the large radial glia of the retina in retinal disease and injury have been well described, that of the retinal astrocytes remains less so. Using modern imaging technology to describe the structural remodeling of retinal astrocytes after retinal detachment is the focus of this paper. We present both a review of critical literature as well as novel work focusing on the responses of astrocytes following rhegmatogenous and serous retinal detachment. The mouse presents a convenient model system in which to study astrocyte reactivity since the Mϋller cell response is muted in comparison to other species thereby allowing better visualization of the astrocytes. We also show data from rat, cat, squirrel, and human retina demonstrating similarities and differences across species. Our data from immunolabeling and dye-filling experiments demonstrate previously undescribed morphological characteristics of normal astrocytes and changes induced by detachment. Astrocytes not only upregulate GFAP, but structurally remodel, becoming increasingly irregular in appearance, and often penetrating deep into neural retina. Understanding these responses, their consequences, and what drives them may prove to be an important component in improving visual outcome in a variety of therapeutic situations. Our data further supports the concept that astrocytes are important players in the retina’s overall response to injury and disease.

Concepts: Neuron, Retina, Retinitis pigmentosa, Diabetic retinopathy, Retinal detachment, Glial cells, Macular degeneration, Radial glia


The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment.

Concepts: Nervous system, DNA, Neuron, Neurobiology, Glial cell, Glial cells, Centrosome, Radial glia


Astrocytes are implicated in modulation of neuronal excitability and synaptic function, but it remains unknown if these glial cells can directly control activities of motor circuits to influence complex behaviors in vivo. This study focused on the vital respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) and determined how compromised function of local astrocytes affects breathing in conscious experimental animals (rats). Vesicular release mechanisms in astrocytes were disrupted by virally driven expression of either the dominant-negative SNARE protein or light chain of tetanus toxin. We show that blockade of vesicular release in preBötC astrocytes reduces the resting breathing rate and frequency of periodic sighs, decreases rhythm variability, impairs respiratory responses to hypoxia and hypercapnia, and dramatically reduces the exercise capacity. These findings indicate that astrocytes modulate the activity of CNS circuits generating the respiratory rhythm, critically contribute to adaptive respiratory responses in conditions of increased metabolic demand and determine the exercise capacity.

Concepts: Protein, Neuron, Bacteria, Pulmonology, Myelin, Glial cell, Glial cells, Gap junction


Cutaneous wound healing is a complex process that aims to re-establish the original structure of the skin and its functions. Among other disorders, peripheral neuropathies are known to severely impair wound healing capabilities of the skin, revealing the importance of skin innervation for proper repair. Here, we report that peripheral glia are crucially involved in this process. Using a mouse model of wound healing, combined with in vivo fate mapping, we show that injury activates peripheral glia by promoting de-differentiation, cell-cycle re-entry and dissemination of the cells into the wound bed. Moreover, injury-activated glia upregulate the expression of many secreted factors previously associated with wound healing and promote myofibroblast differentiation by paracrine modulation of TGF-β signalling. Accordingly, depletion of these cells impairs epithelial proliferation and wound closure through contraction, while their expansion promotes myofibroblast formation. Thus, injury-activated glia and/or their secretome might have therapeutic potential in human wound healing disorders.

Concepts: DNA, Gene expression, Scar, Wound healing, Regulation of gene expression, Skin, Glial cell, Glial cells


Individuals with autism who show high abilities are called savants. Whereas in their brains a disconnection in and between neural networks has been identified, savantism is yet poorly understood. Focusing on astrocyte domain organization, it is hypothesized that local astrocyte mega-organizations may be responsible for exerting high capabilities in brains of autistic savants. Astrocytes, the dominant glial cell type, modulate synaptic information transmission. Each astrocyte is organized in non-overlapping domains. Formally, each astrocyte contacting n-neurons with m-synapses via its processes generates dynamic domains of synaptic interactions based on qualitative computation criteria, and hereby it structures neuronal information processing. If the number of processes is genetically significantly increased, these astrocytes operate in a mega-domain with a higher complexitiy of computation. From this model savant abilities are deduced.

Concepts: Nervous system, Neuron, Autism, Myelin, Glial cells, Gap junction, Savant syndrome, Savant


PURPOSE: Muller glia respond to retinal injury by a reactive gliosis but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the non-mammalian retina, however, Muller glia act as stem/progenitor cells. Here, we test the function of Wnt signaling in the post-injury retina, focusing on its ability to influence mammalian Muller cell de-differentiation, proliferation and neurogenesis. METHODS: A Nd:YAG laser was used to create light burns on the retina of Axin2(LacZ/+) Wnt reporter mice. At various timepoints after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries were also created in Axin2(LacZ/LacZ) mice, and the effect of potentiated Wnt signaling on retinal repair was assessed. RESULTS: A subpopulation of mammalian Muller cells are Wnt responsive and when Wnt signaling is increased these cells showed enchanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of Wnt negative regulator Axin2, Muller cells proliferate after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Muller cells also exhibited long-term survival and in some cases, expressed the rod photoreceptor marker, Rhodopsin. CONCLUSIONS: The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Muller cells to proliferate and de-differentiate into RPCs. These data raise the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.

Concepts: Neuron, Retina, Myelin, Glial cell, Glial cells, Radial glia, Gliosis, Muller glia


Hypoxia has been shown to promote inflammation, including the release of proinflammatory cytokines, but it is poorly investigated how hypoxia directly affects inflammasome signaling pathways. To explore whether hypoxic stress modulates inflammasome activity, we examined the effect of cobalt chloride (CoCl2)-induced hypoxia on caspase-1 activation in primary mixed glial cultures of the neonatal mouse brain. Unexpectedly, hypoxia induced by oxygen-glucose deprivation or CoCl2 treatment failed to activate caspase-1 in microglial BV-2 cells and primary mixed glial cultures. Of particular interest, CoCl2-induced hypoxic condition considerably inhibited NLRP3-dependent caspase-1 activation in mixed glial cells, but not in bone marrow-derived macrophages. CoCl2-mediated inhibition of NLRP3 inflammasome activity was also observed in the isolated brain microglial cells, but CoCl2 did not affect poly dA:dT-triggered AIM2 inflammasome activity in mixed glial cells. Our results collectively demonstrate that CoCl2-induced hypoxia may negatively regulate NLRP3 inflammasome signaling in brain glial cells, but its physiological significance remains to be determined.

Concepts: Immune system, Neuron, Atherosclerosis, Effect, Affect, Glial cell, Glial cells, Microglia


Astrocytes, the star shaped glial cells, are known to possess supportive and homeostatic role for the neurons. Recently, reactive gliosis, which involves alterations in functioning and phenotype of different glial cells, has been implicated in Alzheimer’s Disease (AD). Studies have revealed that astrocyte response to gross tissue damaging injury leads to anisomorphic astrogliosis reinforcing a cascade of events, eventually increasing the pathogenesis of AD and many other neurodegenerative disorders. This review presents the involvement of reactive astrocytes in reduced Aβ clearance and in neuro-neglect hypothesis. Understanding of reactivity and fundamental biology of astrocytes may open new avenues of alternative treatments and therapeutic strategies targeting astrocytes and related events for the treatment of AD.

Concepts: Nervous system, Neuron, Neurology, Neurodegenerative disorders, Glial cell, Glial cells, Gap junction, Gliosis


Peripheral nerve gap defects lead to significant loss of sensory or motor function. Tissue engineering has become an important alternative to nerve repair. Sericin, a major component of silk, is a natural protein whose value in tissue engineering has just begun to be explored. Here, the first time use of sericin in vivo is reported as a long-term implant for peripheral nerve regeneration. A sericin nerve guidance conduit is designed and fabricated. This conduit is highly porous with mechanical strength matching peripheral nerve tissue. It supports Schwann cell proliferation and is capable of up-regulating the transcription of glial cell derived neurotrophic factor and nerve growth factor in Schwann cells. The sericin conduit wrapped with a silicone conduit (sericin/silicone double conduits) is used for bridging repair of a 5 mm gap in a rat sciatic nerve transection model. The sericin/silicone double conduits achieve functional recovery comparable to that of autologous nerve grafting as evidenced by drastically improved nerve function and morphology. Importantly, this improvement is mainly attributed to the sericin conduit as the silicone conduit alone only produces marginal functional recovery. This sericin/silicone-double-conduit strategy offers an efficient and valuable alternative to autologous nerve grafting for repairing damaged peripheral nerve.

Concepts: Action potential, Myelin, Neurobiology, Glial cell, Glial cells, Nerve growth factor, Schwann cell, Theodor Schwann