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Bernadette Basilico, Francesca Pagani, Alfonso Grimaldi, Barbara Cortese, Silvia Di Angelantonio, Laetitia Weinhard, Cornelius Gross, Cristina Limatola, Laura Maggi, Davide Ragozzino
Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3-CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages...
November 11, 2018: Glia
Chun-Ta Huang, Seu-Hwa Chen, Shih-Chang Lin, Wei-Ting Chen, June-Horng Lue, Yi-Ju Tsai
Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)-induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests were conducted. Immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of microglial and mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, activation...
November 11, 2018: Glia
Wolfgang J Streit, Heiko Braak, Kelly Del Tredici, Judith Leyh, Julia Lier, Habibeh Khoshbouei, Christian Eisenlöffel, Wolf Müller, Ingo Bechmann
Sporadic Alzheimer's disease (AD) is marked by a lengthy preclinical phase during which patients are nonsymptomatic but show pathology in variable manifestations. Whether or not neuroinflammation occurs in such nondemented individuals is unknown. We evaluated the medial temporal lobe of 66 nondemented subjects, aged 42-93, in terms of tau pathology, Aβ deposition, and microglial activation. We show that 100% of subjects had neurofibrillary degeneration (NFD), 35% had Aβ deposits, and 8% revealed microglial activation in individuals where early amyloid formation was apparent by Congo Red staining...
November 11, 2018: Glia
Scott Dyck, Hardeep Kataria, Khashayar Akbari-Kelachayeh, Jerry Silver, Soheila Karimi-Abdolrezaee
Following spinal cord injury (SCI), the population of mature oligodendrocytes undergoes substantial cell death; promoting their preservation and replacement is a viable strategy for preserving axonal integrity and white matter repair in the injured spinal cord. Dramatic upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) is shown to pose an obstacle to endogenous repair processes, and targeting CSPGs improves functional recovery after SCI. However, the cellular and molecular mechanisms underlying the inhibitory effects of CSPGs remain largely undefined...
November 5, 2018: Glia
Dolores Piniella, Elena Martínez-Blanco, Ignacio Ibáñez, David Bartolomé-Martín, Eva Porlan, Javier Díez-Guerra, Cecilio Giménez, Francisco Zafra
We used proximity-dependent biotin identification (BioID) to find proteins that potentially interact with the major glial glutamate transporter, GLT-1, and we studied how these interactions might affect its activity. GTPase Rac1 was one protein identified, and interfering with its GTP/GDP cycle in mixed primary rat brain cultures affected both the clustering of GLT-1 at the astrocytic processes and the transport kinetics, increasing its uptake activity at low micromolar glutamate concentrations in a manner that was dependent on the effector kinase PAK1 and the actin cytoskeleton...
November 5, 2018: Glia
Mauricio Dos-Santos-Pereira, Leonardo Acuña, Sabah Hamadat, Jeremy Rocca, Florencia González-Lizárraga, Rosana Chehín, Julia Sepulveda-Diaz, Elaine Del-Bel, Rita Raisman-Vozari, Patrick P Michel
When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α-Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of αS but not with the native monomeric protein...
November 5, 2018: Glia
Ljiljana Nikolic, Weida Shen, Paola Nobili, Anaïs Virenque, Lauriane Ulmann, Etienne Audinat
Epilepsy is characterized by unpredictable recurrent seizures resulting from abnormal neuronal excitability. Increasing evidence indicates that aberrant astrocyte signaling to neurons plays an important role in driving the network hyperexcitability, but the underlying mechanism that alters glial signaling in epilepsy remains unknown. Increase in glutamate release by astrocytes participates in the onset and progression of seizures. Epileptic seizures are also accompanied by increase of tumor necrosis factor alpha (TNFα), a cytokine involved in the regulation of astrocyte glutamate release...
November 5, 2018: Glia
Hwan Tae Park, Jong Kuk Kim, Nicolas Tricaud
Myelinating Schwann cells undergo irreversible demyelination in many demyelinating neuropathies that show complete demyelination of the internode. Dedifferentiation, reprogramming, and myelin clearance processes-which are specifically discussed in this article-appear to be shared by various demyelinating peripheral conditions, such as Wallerian degeneration, immune-mediated, and toxic demyelinating diseases. We propose to introduce the concept of the "demyelinating Schwann cell (DSC)" as a novel cell phenotype, which has specific properties required for myelin sheath clearance...
October 30, 2018: Glia
Komudi Singh, Kim Han, Sharada Tilve, Kaiyuan Wu, Herbert M Geller, Michael N Sack
Loss of substantia nigra dopaminergic neurons results in Parkinson disease (PD). Degenerative PD usually presents in the seventh decade whereas genetic disorders, including mutations in PARK2, predispose to early onset PD. PARK2 encodes the parkin E3 ubiquitin ligase which confers pleotropic effects on mitochondrial and cellular fidelity and as a mediator of endoplasmic reticulum (ER) stress signaling. Although the majority of studies investigating ameliorative effects of parkin focus on dopaminergic neurons we found that astrocytes are enriched with parkin...
October 30, 2018: Glia
Kristina G Witcher, Chelsea E Bray, Julia E Dziabis, Daniel B McKim, Brooke N Benner, Rachel K Rowe, Olga N Kokiko-Cochran, Phillip G Popovich, Jonathan Lifshitz, Daniel S Eiferman, Jonathan P Godbout
Microglia undergo dynamic structural and transcriptional changes during the immune response to traumatic brain injury (TBI). For example, TBI causes microglia to form rod-shaped trains in the cerebral cortex, but their contribution to inflammation and pathophysiology is unclear. The purpose of this study was to determine the origin and alignment of rod microglia and to determine the role of microglia in propagating persistent cortical inflammation. Here, diffuse TBI in mice was modeled by midline fluid percussion injury (FPI)...
October 30, 2018: Glia
Jinming Han, Keying Zhu, Xing-Mei Zhang, Robert A Harris
Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons...
October 30, 2018: Glia
Akiko Takeda, Youichi Shinozaki, Kenji Kashiwagi, Nobuhiko Ohno, Kei Eto, Hiroaki Wake, Junichi Nabekura, Schuichi Koizumi
Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1-tTA::DTAtetO/tetO mice...
October 29, 2018: Glia
Allison R Najafi, Joshua Crapser, Shan Jiang, Winnie Ng, Ali Mortazavi, Brian L West, Kim N Green
Microglia are the resident immune cell of the central nervous system (CNS), and serve to protect and maintain the local brain environment. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R); administration of CSF1R inhibitors that cross the blood brain barrier (BBB) lead to the elimination of up to 99% of microglia, depending on CNS exposure and treatment duration. Once microglia are depleted, withdrawal of inhibitor stimulates repopulation of the entire CNS with new cells, conceivably enabling a therapeutic strategy for beneficial renewal of the entire microglial tissue...
October 28, 2018: Glia
Andrea Mölders, Angela Koch, Raphael Menke, Nikolaj Klöcker
Astrocytes form the largest class of glial cells in the central nervous system. They serve plenty of diverse functions that range from supporting the formation and proper operation of synapses to controlling the blood-brain barrier. For many of them, the expression of ionotropic glutamate receptors of the AMPA subtype (AMPARs) in astrocytes is of key importance. AMPARs form as macromolecular protein complexes, whose composition of the pore-lining GluA subunits and of an extensive set of core and peripheral complex constituents defines both their trafficking and gating behavior...
October 28, 2018: Glia
Raquel Blazquez, Darius Wlochowitz, Alexander Wolff, Stefanie Seitz, Astrid Wachter, Julia Perera-Bel, Annalen Bleckmann, Tim Beißbarth, Gabriela Salinas, Markus J Riemenschneider, Martin Proescholdt, Matthias Evert, Kirsten Utpatel, Laila Siam, Bawarjan Schatlo, Marko Balkenhol, Christine Stadelmann, Hans-Ulrich Schildhaus, Ulrike Korf, Eileen Reinz, Stefan Wiemann, Elena Vollmer, Mathias Schulz, Uwe Ritter, Uwe K Hanisch, Tobias Pukrop
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment...
October 25, 2018: Glia
Anan Shtaya, Ahmed-Ramadan Sadek, Malik Zaben, Gerald Seifert, Ashley Pringle, Christian Steinhäuser, William Peter Gray
Neurogenesis is sustained throughout life in the mammalian brain, supporting hippocampus-dependent learning and memory. Its permanent alteration by status epilepticus (SE) is associated with learning and cognitive impairments. The mechanisms underlying the initiation of altered neurogenesis after SE are not understood. Glial fibrillary acidic protein-positive radial glia (RG)-like cells proliferate early after SE, but their proliferation dynamics and signaling are largely unclear. We have previously reported a polarized distribution of AMPA receptors (AMPARs) on RG-like cells in vivo and postulated that these may signal their proliferation...
October 25, 2018: Glia
Laurent Methot, Vincent Soubannier, Robert Hermann, Erin Campos, Sally Li, Stefano Stifani
Nuclear factor-kappaB (NF-κB) is activated in neural progenitor cells in the developing murine cerebral cortex during the neurogenic phase, when it acts to prevent premature neuronal differentiation. Here we show that NF-κB activation continues in mouse neocortical neural progenitor cells during the neurogenic-to-gliogenic switch. Blockade of endogenous NF-κB activity during neocortical gliogenesis leads to the formation of supernumerary committed gliogenic progenitors and premature glial cell differentiation...
October 19, 2018: Glia
Christos P Papaneophytou, Elena Georgiou, Christos Karaiskos, Irene Sargiannidou, Kyriaki Markoullis, Mona M Freidin, Charles K Abrams, Kleopas A Kleopa
Gap junctions (GJs) coupling oligodendrocytes to astrocytes and to other oligodendrocytes are formed mainly by connexin47 (Cx47) and a smaller portion by connexin32 (Cx32). Mutations in both connexins cause inherited demyelinating disorders, but their expression is also disrupted in multiple sclerosis (MS). To clarify whether the loss of either Cx47 or Cx32 could modify the outcome of inflammation and myelin loss, we induced experimental autoimmune encephalomyelitis (EAE) in fully backcrossed Cx32 knockout (KO) and Cx47KO mice and compared their outcome with wild type (WT, C57BI/6 N) mice...
October 16, 2018: Glia
Jennetta W Hammond, Wen Q Qiu, Daniel F Marker, Jeffrey M Chamberlain, Will Greaves-Tunnell, Matthew J Bellizzi, Shao-Ming Lu, Harris A Gelbard
Microglial activation, increased proinflammatory cytokine production, and a reduction in synaptic density are key pathological features associated with HIV-associated neurocognitive disorders (HAND). Even with combination antiretroviral therapy (cART), more than 50% of HIV-positive individuals experience some type of cognitive impairment. Although viral replication is inhibited by cART, HIV proteins such as Tat are still produced within the nervous system that are neurotoxic, involved in synapse elimination, and provoke enduring neuroinflammation...
October 16, 2018: Glia
Wen-Feng Su, Fan Wu, Zi-Han Jin, Yun Gu, Ying-Ting Chen, Ying Fei, Hui Chen, Ya-Xian Wang, Ling-Yan Xing, Ya-Yu Zhao, Ying Yuan, Xin Tang, Gang Chen
Of the seven P2X receptor subtypes, P2X4 receptor (P2X4R) is widely distributed in the central nervous system, including in neurons, astrocytes, and microglia. Accumulating evidence supports roles for P2X4R in the central nervous system, including regulating cell excitability, synaptic transmission, and neuropathic pain. However, little information is available about the distribution and function of P2X4R in the peripheral nervous system. In this study, we find that P2X4R is mainly localized in the lysosomes of Schwann cells in the peripheral nervous system...
October 11, 2018: Glia
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