Yoshiki Hatashita, Zhaofa Wu, Hirotaka Fujita, Takuma Kumamoto, Jean Livet, Yulong Li, Manabu Tanifuji, Takafumi Inoue
Astrocytes participate in information processing by releasing neuroactive substances termed gliotransmitters, including ATP. Individual astrocytes come into contact with thousands of synapses with their ramified structure, but the spatiotemporal dynamics of ATP gliotransmission remains unclear, especially in physiological brain tissue. Using a genetically encoded fluorescent sensor, GRABATP1.0 , we discovered that extracellular ATP increased locally and transiently in absence of stimuli in neuron-glia co-cultures, cortical slices, and the anesthetized mouse brain...
June 1, 2023: Glia
Giacomo Gravina, Maryam Ardalan, Tetyana Chumak, Halfdan Rydbeck, Xiaoyang Wang, Carl Joakim Ek, Carina Mallard
Staphylococcus epidermidis (S. epidermidis) is the most common nosocomial pathogen in preterm infants and associated with increased risk of cognitive delay, however, underlying mechanisms are unknown. We employed morphological, transcriptomic and physiological methods to extensively characterize microglia in the immature hippocampus following S. epidermidis infection. 3D morphological analysis revealed activation of microglia after S. epidermidis. Differential expression combined with network analysis identified NOD-receptor signaling and trans-endothelial leukocyte trafficking as major mechanisms in microglia...
May 29, 2023: Glia
Natascha S Vana, Karen M J van Loo, Ashley J van Waardenberg, Monika Tießen, Silvia Cases-Cunillera, Wenjing Sun, Anne Quatraccioni, Susanne Schoch, Dirk Dietrich
Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, a process that may be tuned by neuronal activity, possibly via synaptic connections to OPCs. However, a developmental role of synaptic signaling to OPCs has so far not been shown unequivocally. To address this question, we comparatively analyzed functional and molecular characteristics of highly proliferative and migratory OPCs in the embryonic brain. Embryonic OPCs in mice (E18.5) shared the expression of voltage-gated ion channels and their dendritic morphology with postnatal OPCs, but almost completely lacked functional synaptic currents...
May 25, 2023: Glia
Jo Bossuyt, Yana Van Den Herrewegen, Liam Nestor, An Buckinx, Dimitri De Bundel, Ilse Smolders
Insights into the role astrocytes and microglia play in normal and diseased brain functioning has expanded drastically over the last decade. Recently, chemogenetic tools have emerged as cutting-edge techniques, allowing targeted and spatiotemporal precise manipulation of a specific glial cell type. As a result, significant advances in astrocyte and microglial cell function have been made, showing how glial cells can intervene in central nervous system (CNS) functions such as cognition, reward and feeding behavior in addition to their established contribution in brain diseases, pain, and CNS inflammation...
May 24, 2023: Glia
Wen-Jun Zhang, Chang-Lei Wu, Ji-Peng Liu
Tumor erosion and metastasis can invade surrounding tissues, damage nerves, and sensitize the peripheral primary receptors, inducing pain, which can potentially worsen the suffering of patients with cancer. Reception and transmission of sensory signal receptors, abnormal activation of primary sensory neurons, and activation of glial cells are involved in cancer pain. Therefore, exploring promising therapeutic methods to suppress cancer pain is of great significance. Various studies have found that the use of functionally active cells is a potentially effective way to relieve pain...
May 23, 2023: Glia
Nicole Pukos, Christina M Marion, W David Arnold, Benjamin T Noble, Phillip G Popovich, Dana M McTigue
Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post-injury (wpi). We also detected new myelin formation over 2 months post-injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination. We also examined electrophysiological changes during peak oligogenesis and a potential mechanism driving OL progenitor cell (OPC) contact with axons...
May 20, 2023: Glia
Dimitrios Kleidonas, Matthias Kirsch, Geoffroy Andrieux, Dietmar Pfeifer, Melanie Boerries, Andreas Vlachos
The pro-inflammatory cytokine tumor necrosis factor α (TNFα) tunes the capacity of neurons to express synaptic plasticity. It remains, however, unclear how TNFα mediates synaptic positive (=change) and negative (=stability) feedback mechanisms. We assessed effects of TNFα on microglia activation and synaptic transmission onto CA1 pyramidal neurons of mouse organotypic entorhino-hippocampal tissue cultures. TNFα mediated changes in excitatory and inhibitory neurotransmission in a concentration-dependent manner, where low concentration strengthened glutamatergic neurotransmission via synaptic accumulation of GluA1-only-containing AMPA receptors and higher concentration increased inhibition...
May 19, 2023: Glia
Yanan Chen, Songhua Quan, Vaibhav Patil, Rejani B Kunjamma, Haley M Tokars, Eric D Leisten, Godwin Joy, Samantha Wills, Jonah R Chan, Yvette C Wong, Brian Popko
central nervous system (CNS) inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation. However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway...
May 19, 2023: Glia
Savannah M Rocha, Kelly S Kirkley, Debotri Chatterjee, Tawfik A Aboellail, Richard J Smeyne, Ronald B Tjalkens
Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide, with a greater prevalence in men than women. The etiology of PD is largely unknown, although environmental exposures and neuroinflammation are linked to protein misfolding and disease progression. Activated microglia are known to promote neuroinflammation in PD, but how environmental agents interact with specific innate immune signaling pathways in microglia to stimulate conversion to a neurotoxic phenotype is not well understood...
May 18, 2023: Glia
Daniela Madeira, Cátia R Lopes, Ana P Simões, Paula M Canas, Rodrigo A Cunha, Paula Agostinho
Astrocytes are wired to bidirectionally communicate with neurons namely with synapses, thus shaping synaptic plasticity, which in the hippocampus is considered to underlie learning and memory. Adenosine A2A receptors (A2A R) are a potential candidate to modulate this bidirectional communication, since A2A R regulate synaptic plasticity and memory and also control key astrocytic functions. Nonetheless, little is known about the role of astrocytic A2A R in synaptic plasticity and hippocampal-dependent memory...
May 15, 2023: Glia
Baoyan Fan, Michael Chopp, Yi Zhang, Xinli Wang, Amy Kemper, Zheng Gang Zhang, Xian Shuang Liu
Schwann cells (SCs) form myelin and provide metabolic support for axons, and are essential for normal nerve function. Identification of key molecules specific to SCs and nerve fibers may provide new therapeutic targets for diabetic peripheral neuropathy (DPN). Argonaute2 (Ago2) is a key molecular player that mediates the activity of miRNA-guided mRNA cleavage and miRNA stability. Our study found that Ago2 knockout (Ago2-KO) in proteolipid protein (PLP) lineage SCs in mice resulted in a significant reduction of nerve conduction velocities and impairments of thermal and mechanical sensitivities...
May 13, 2023: Glia
Kamil Sebastian Rosiewicz, Bakhrom Muinjonov, Séverine Kunz, Helena Radbruch, Jessy Chen, René Jüttner, Janis Kerkering, Julia Ucar, Tadhg Crowley, Ben Wielockx, Friedemann Paul, Marlen Alisch, Volker Siffrin
Astrocytes constitute the parenchymal border of the blood-brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases. We investigated transgenic mice with astrocyte-specific activation of the hypoxia-response program by deleting the oxygen sensors, HIF prolyl-hydroxylase domains 2 and 3 (Phd2/3)...
May 4, 2023: Glia
Nataliya Tokarska, Justin M A Naniong, Jayne M Johnston, Hannah E Salapa, Gillian D Muir, Michael C Levin, Bogdan F Popescu, Valerie M K Verge
Remyelination and neurodegeneration prevention mitigate disability in Multiple Sclerosis (MS). We have shown acute intermittent hypoxia (AIH) is a novel, non-invasive and effective therapy for peripheral nerve repair, including remyelination. Thus, we posited AIH would improve repair following CNS demyelination and address the paucity of MS repair treatments. AIH's capacity to enhance intrinsic repair, functional recovery and alter disease course in the experimental autoimmune encephalomyelitis (EAE) model of MS was assessed...
May 3, 2023: Glia
Ryosuke Kamei, Shigeo Okabe
The phagocytosis of dead cells by microglia is essential in brain development and homeostasis. However, the mechanism underlying the efficient removal of cell corpses by ramified microglia remains poorly understood. Here, we investigated the phagocytosis of dead cells by ramified microglia in the hippocampal dentate gyrus, where adult neurogenesis and homeostatic cell clearance occur. Two-color imaging of microglia and apoptotic newborn neurons revealed two important characteristics. Firstly, frequent environmental surveillance and rapid engulfment reduced the time required for dead cell clearance...
April 27, 2023: Glia
Aimei Liu, Lingtai Yu, Xuejun Li, Kejiao Zhang, Wei Zhang, Kwok-Fai So, Fadel Tissir, Yibo Qu, Libing Zhou
Neural repair is highly influenced by reactive astrocytes. Atypical cadherin Celsr2 regulates neuron development and axon regeneration, while its role in glial cells remains unexplored. In this study, we show that Celsr2 is highly expressed in spinal astrocytes of adult mice, and knockout of Celsr2 results in reactive astrocytes with longer protrusions preferentially orientated towards lesion borders in culture scratch assay and injured spinal cord, and elevation of total and active Cdc42 and Rac1 protein in western blots...
April 26, 2023: Glia
B R Kondiles, R L Murphy, A J Widman, S I Perlmutter, P J Horner
Neural activity and learning lead to myelin sheath plasticity in the intact central nervous system (CNS), but this plasticity has not been well-studied after CNS injury. In the context of spinal cord injury (SCI), demyelination occurs at the lesion site and natural remyelination of surviving axons can take months. To determine if neural activity modulates myelin and axon plasticity in the injured, adult CNS, we electrically stimulated the contralesional motor cortex at 10 Hz to drive neural activity in the corticospinal tract of rats with sub-chronic spinal contusion injuries...
April 25, 2023: Glia
Victoria G Hernandez, Kendra J Lechtenberg, Todd C Peterson, Li Zhu, Tawaun A Lucas, Karen P Bradshaw, Justice O Owah, Alanna I Dorsey, Andrew J Gentles, Marion S Buckwalter
Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and long-term disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period, hours after stroke, have not been elucidated. We used the RiboTag technique to obtain microglia and astrocyte-derived mRNA transcripts in a hyperacute (4 h) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation...
April 17, 2023: Glia
TrangKimberly Thu Nguyen, Chad R Camp, Juleva K Doan, Stephen F Traynelis, Steven A Sloan, Randy A Hall
Astrocyte maturation is crucial to proper brain development and function. This maturation process includes the ramification of astrocytic morphology and the establishment of astrocytic domains. While this process has been well-studied, the mechanisms by which astrocyte maturation is initiated are not well understood. GPR37L1 is an astrocyte-specific G protein-coupled receptor (GPCR) that is predominantly expressed in mature astrocytes and has been linked to the modulation of seizure susceptibility in both humans and mice...
April 8, 2023: Glia
Koby Baranes, Nataly Hastings, Saifur Rahman, Noah Poulin, Joana M Tavares, Wei-Li Kuan, Najeeb Syed, Meik Kunz, Kevin Blighe, T Grant Belgard, Mark R N Kotter
Increasing evidence indicates that cellular identity can be reduced to the distinct gene regulatory networks controlled by transcription factors (TFs). However, redundancy exists in these states as different combinations of TFs can induce broadly similar cell types. We previously demonstrated that by overcoming gene silencing, it is possible to deterministically reprogram human pluripotent stem cells directly into cell types of various lineages. In the present study we leverage the consistency and precision of our approach to explore four different TF combinations encoding astrocyte identity, based on previously published reports...
April 8, 2023: Glia
Kazi Atikur Rahman, Marta Orlando, Ayub Boulos, Ewa Andrzejak, Dietmar Schmitz, Noam E Ziv, Harald Prüss, Craig C Garner, Aleksandra Ichkova
Autoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs...
April 7, 2023: Glia
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