pinecone/core-2020-05-10-deduplication huggingface dataset:
Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death

After the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipase activity and cytosolic PLA(2)-IV alpha protein expression increased. However, the expression of secreted isoforms of PLA(2) (sPLA(2)) and their possible roles in oligodendrocyte death following SCI remained unclear. Here we report that mRNAs extracted 15 min, 4 h, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA(2)-IIA and IIE at 4 h after injury. In contrast, SCI induced down regulation of sPLA(2)-X, and no change in sPLA(2)-IB, IIC, V, and XIIA expression. At the lesion site, sPLA(2)-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA(2)-IIA (0.01, 0.1, or 2 microM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA(2)-IIA inhibitor, before a 30 min H(2)O(2) injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 h. Similarly, pretreatment with S3319 before injury with IL-1 beta and TNFalpha prevented cell death and loss of oligodendrocyte processes at 72 h. Collectively, these findings suggest that sPLA(2)-IIA and IIE are increased following SCI, that increased sPLA(2)-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA(2) can create sparing of oligodendrocytes in two distinct injury models. Therefore, sPLA(2)-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI
Expression of the HGF receptor c-met by macrophages in experimental autoimmune encephalomyelitis

Hepatocyte growth factor (HGF) is a pleiotropic cytokine able to evoke a wide array of cellular responses including proliferation, migration, and survival through activation of its receptor c-met. Various types of leukocytes have been described to express c-met suggesting that HGF/c-met signaling may directly influence leukocyte responses in inflammation. We have investigated the HGF/c-met pathway in experimental autoimmune encephalomyelitis (EAE), a common mouse model of multiple sclerosis (MS), in which macrophages play a dual role, contributing directly to CNS damage at disease onset but promoting recovery during remission by removing myelin debris. Here we show that during EAE both HGF and c-met are expressed in the CNS and that c-met is activated. We subsequently demonstrate that c-met is primarily expressed in inflammatory lesions by macrophages and a small number of dendritic cells (DCs) and oligodendrocyte progenitor cells (OPCs) but not by microglia or T cells. Complementary in vitro experiments show that only LPS and TNFalpha, but not IL-6, IL-10, or IL-13, are able to induce c-met expression in macrophages. In addition, using TNF signaling deficient macrophages we demonstrate that LPS and TNFalpha induce c-met through distinct pathways. Furthermore, TNFalpha- and LPS-induced c-met is functional because treatment of macrophages with recombinant HGF results in rapid phosphorylation of c-met. Interestingly, HGF/c-met signaling does not modulate cytokine expression, phagocytosis, or antigen presentation but promotes proliferation of activated macrophages. Taken together, our data indicate a pro-inflammatory role for the HGF/c-met pathway in EAE rather than a role in the initiation of repair mechanisms. (c) 2009 Wiley-Liss, Inc
Olfactory ensheathing cell membrane properties are shaped by connectivity

Olfactory ensheathing cells (OECs) have been repeatedly implicated in mediating plasticity, particularly in situ in the olfactory nerve where they support the extension of olfactory sensory neuron (OSNs) axons from the olfactory epithelium to the olfactory bulb (OB). OECs are specialized glia whose processes surround OSN axon fascicles within the olfactory nerve and across the OB surface. Despite their purported importance in promoting axon extension, and following transplants, little is known about either morphology or biophysical properties of OECs in situ. In particular, cell-cell interactions that may influence OEC function are largely unexplored. Here, we studied OEC connectivity and morphology in slice preparations, preserving tissue structure and cell-cell interactions. Our analyses showed that OECs form a matrix of cellular projections surrounding axons, unique among glia, and express high levels of connexin-43. Lucifer Yellow injections revealed selective dye coupling among small subgroups of OECs. Two types of OECs were biophysically distinguished with whole cell voltage clamp recordings: 1) with low input resistance (Ri), linear current profiles, and frequently dye coupled; and 2) with high Ri, non-linear current profiles, and infrequent dye coupling. Pharmacological blockade of gap junctions changed OEC membrane properties such that linear OECs became non-linear. Double recordings indicated that the appearance of the non-linear current profile was associated with the loss of electrical coupling between OECs. We conclude that the diversity of OEC current profiles can be explained by differences in gap junction connectivity and discuss implications of this diversity for OEC influences on axon growth and excitability.Fil: Rela, Lorena. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bordey, Angelique. University of Yale; Estados UnidosFil: Greer, Charles A.. University of Yale; Estados Unido
Peroxisome proliferator-activated receptor γ ligands regulate neural stem cell proliferation and differentiation in vitro and in vivo

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological and pathological situations. Its role in the central nervous system has been under intense analysis during the last years. Here we show a novel function for PPARγ in controlling stem cell expansion in the adult mammalian brain. Adult rats treated with pioglitazone, a specific ligand of PPARγ, had elevated numbers of proliferating progenitor cells in the subventricular zone and the rostral migratory stream. Electron microscopy analysis also showed important changes in the subventricular zone ultrastructure of pioglitazone-treated animals including an increased number of migratory cell chains. These results were further confirmed in vitro. Neurosphere assays revealed significant increases in the number of neurosphere forming cells from pioglitazone- and rosiglitazone (two specific ligands of PPARγ receptor)-treated cultures that exhibited enhanced capacity for cell migration and differentiation. The effects of pioglitazone were blocked by the PPARγ receptor antagonists GW9662 and T0070907, suggesting that its effects are mediated by a mechanism dependent on PPARγ activation. These results indicate for the first time that activation of PPARγ receptor directly regulates proliferation, differentiation, and migration of neural stem cells in vivo. © 2010 Wiley-Liss, Inc.This work was supported by the Ministerio de Educacion y Ciencia [SAF2007-62811 to A.P.-C and SAF2008-01274 to J.M.G.-V.] J.A.M-G. is a post-doctoral fellow of Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, founded by the Instituto de Salud Carlos III.Peer Reviewe
Roles of aquaporin-4 and Kir4.1 in brain water and potassium homeostasis :  lessons from knockout mice

List of papers. Papers I and IV are removed from the thesis due to copyright restrictions.<br><br>

Paper I 
Haj-Yasein NN, Jensen V, Vindedal GF, Gundersen GA, Klungland A, Ottersen OP, Hvalby O, Nagelhus EA.
Evidence that compromised K+ spatial buffering contributes to the epileptogenic effect of mutations in the human Kir4.1 gene (KCNJ10).
Glia. 2011 Nov;59(11):1635-42. doi: 10.1002/glia.21205. Epub 2011 Jul 11.
<a href="http://dx.doi.org/10.1002/glia.21205">doi:10.1002/glia.21205</a><br><br>

Paper II 
Haj-Yasein NN, Jensen V, Østby I, Omholt S, Voipio J, Kaila K, Ottersen OP, Hvalby Ø, Nagelhus EA.
Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic
stimulation: a gene deletion study in mouse hippocampus. Submitted.
Glia. 2012, Online Early View. Epub 2012 Mar 14. The definitive version is available at www3.interscience.wiley.com
<a href="http://dx.doi.org/10.1002/glia.22319">doi:10.1002/glia.22319</a><br><br>

Paper III 
Eilert-Olsen M, Haj-Yasein NN, Vindedal GF, Enger R, Gundersen GA, Hoddevik EH, Petersen PH, Haug FM, Skare Ø, Adams ME, Froehner SC, Burkhardt JM, Thoren AE, Nagelhus EA.
Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier.
Glia. 2012 Mar;60(3):432-40. Epub 2011 Nov 30. The definitive version is available at www3.interscience.wiley.com
<a href="http://dx.doi.org/10.1002/glia.22277">doi:10.1002/glia.22277</a><br><br>

Paper IV 
Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare Ø, Laake P, Klungland A, Thorén AE, Burkhardt JM, Ottersen OP, Nagelhus EA.
Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet.
Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17815-20. Epub 2011 Oct 11.
<a href="http://dx.doi.org/10.1073/pnas.1110655108">doi:10.1073/pnas.1110655108</a
Glutamatergic and GABAergic gliotransmission

Glutamatergic and GABAergic gliotransmission is a compilation of studies on the ability of glial cells to release glutamate by exocytosis and GABA by bestrophin 1 channel.
The vesicular glutamate transporters (VGLUTs) are solely found in the membrane of vesicles and selectively transport glutamate into the vesicles. The presence of such proteins is a strong indication of the capability to exocytose glutamate.
In the first study I found significant amount of VGLUT1 in astrocytes of frontal cortex, stratum radiatum of the hippocampus, molecular layers of the hippocampus and the striatum. VGLUT1 was associated with synaptic-like microvesicles (SLMV). The second study revealed VGLUT3 in glial cells of cerebellum, CA3 hippocampus and frontal cortex. VGLUT3 was also associated to SLMV, although not the same vesicle pools as VGLUT1.
The last paper revealed significant, although very small levels of GABA in glial cells of CA1 hippocampus and cerebellum. In glial cells of the same regions there was an indistinguishable level of bestrophin 1 in wild type and bestrophin 1 knock out animals, both on protein and RNA level. These aspects make glial release of GABA through bestrophin 1 unlikely
Two phases of replacement replenish the olfactory ensheathing cell population after injury in postnatal mice

Olfactory ensheathing cells (OECs) support the regeneration of olfactory sensory neurons throughout life, however it remains unclear how OECs respond to a major injury. We have examined the proliferation and migration of OECs following unilateral bulbectomy in postnatal mice. S100߭DsRed and OMP-ZsGreen transgenic mice were used to visualise OECs and olfactory neurons, respectively, and we used the thymidine analogue ethynyl deoxyuridine (EdU) to identify cells that were proliferating at the time of administration. Following unilateral bulbectomy, there was an initial phase of OEC proliferation throughout the olfactory pathway with a peak of proliferation occurring 2-7 days after the injury. A second phase of proliferation also occurred in which precursors localised within the olfactory mucosa divided to replenish the OEC population. We then tracked the positions of OECs that had proliferated and found that there was a progressive increase in OECs in the cavity for at least 12-16 days after injury which could not be accounted for solely by local proliferation of OECs within the cavity. These results suggest that OECs migrated from the peripheral olfactory nerve to populate the mass of cells that filled cavity left by bulbectomy. Our results demonstrate that following injury to the olfactory nervous system, the OEC population is replenished by migration of cells that arise from both local proliferation of OECs throughout the olfactory nerve pathway as well as from precursor cells in the olfactory mucosa.Full Tex
The role of insulin-like growth factors signaling in merlin-deficient human schwannomas.

Loss of the tumor suppressor merlin causes development of the tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas occurring spontaneously or as part of a hereditary disease Neurofibromatosis Type 2 (NF2). Current therapies, (radio) surgery, are not always effective. Therefore, there is a need for drug treatments for these tumors. Schwannomas are the most frequent of merlin-deficient tumors and are hallmark for NF2. Using our in vitro human schwannoma model, we demonstrated that merlin-deficiency leads to increased proliferation, cell-matrix adhesion, and survival. Increased proliferation due to strong activation of extracellular-signal-regulated kinase 1/2 (ERK1/2) is caused by overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) and ErbB2/3 which we successfully blocked with AZD6244, sorafenib, or lapatinib. Schwannoma basal proliferation is, however, only partly dependent on PDGFR-β and is completely independent of ErbB2/3. Moreover, the mechanisms underlying pathological cell-matrix adhesion and survival of schwannoma cells are still not fully understood. Here, we demonstrate that insulin-like growth factor-I receptor (IGF-IR) is strongly overexpressed and activated in human primary schwannoma cells. IGF-I and -II are overexpressed and released from schwannoma cells. We show that ERK1/2 is relevant for IGF-I-mediated increase in proliferation and cell-matrix adhesion, c-Jun N-terminal kinases for increased proliferation and AKT for survival. We demonstrate new mechanisms involved in increased basal proliferation, cell-matrix adhesion, and survival of schwannoma cells. We identified therapeutic targets IGF-IR and downstream PI3K for treatment of schwannoma and other merlin-deficient tumors and show usefulness of small molecule inhibitors in our model. PI3K is relevant for both IGF-IR and previously described PDGFR-β signaling in schwannoma
Sex-related differences of cAMP-specific PDE4B3 mRNA in oligodendrocytes following systemic inflammation

Sex-related differences have been observed in the incidence and severity of several neurological diseases and in sepsis in humans. Cyclic adenosine monophosphate (cAMP) has been shown to play an important role in modulating the inflammatory environment during neuroinflammation and importantly in protecting myelin from excitotoxic cell death. Considering the sexual dimorphism in the functional properties of oligodendrocytes and the importance of a systemic inflammation in the progression of multiple sclerosis, we focused on identifying possible sex-related differences in the alterations previously reported for the two phosphodiesterase4B (PDE4B) splice-variants (PDE4B2 and PDE4B3) mRNA expression during innate neuroinflammation. PDE4A, PDE4B, and PDE4D are present in oligodendrocytes and we have previously reported that PDE4B3 mRNA is readily expressed in both oligodendrocytes and neurons. In this study, we analyzed the influence of an intraperitoneal lipopolysaccharide injection on the distribution pattern and expression levels of the PDE4B mRNA splicing variants in both male and female mice brains. Clear differences were observed in PDE4B2 and PDE4B3 mRNA expression levels in males compared with females in a time-dependent manner. Furthermore, we observed that the clear downregulation of PDE4B3 mRNA was reflected in a lower percentage of oligodendrocytes positive for this transcript which correlated with a decrease in inducible cAMP early repressor expression in female corpus callosum. © 2012 Wiley Periodicals, Inc.Grant sponsor: Spanish Ministerio de Educación y Ciencia; Grant number: SAF2006-10243; Grant sponsor: Ministerio de Ciencia e Innovación; Grant numbers: SAF 2009-11052, PI-10/01874; Grant sponsor: Generalitat de Catalunya; Grant number: SGR2009/220; Grant sponsor: FEDER Funds (European Union).Peer Reviewe
Regulation of microglia development and homeostasis

Microglia represent the resident macrophages of the central nervous system (CNS) and account for 10% of the adult glial cell population in the normal brain. Although microglial cells are thought to contribute to most pathological conditions including CNS infections, neuroinflammatory lesions, brain tumors, and neurodegenerative diseases, their exact role in CNS development, homeostasis, and disease remains poorly understood. In contrast to most macrophage populations, microglia survive high-dose ionizing radiation and maintain themselves locally and independently of circulating precursors in the steady state. However, controversies remain on the origin of microglia in the brain and whether they could potentially be repopulated by circulating myeloid precursors after brain injury. Microglia-targeted therapies through the use of genetically modified circulating hematopoietic cells proved to be a promising therapeutic strategy for the treatment of brain diseases. It is thus of great importance to understand the contribution and developmental cues of circulating myeloid cells as potential microglia progenitors to the adult pool of microglia in the steady state and under inflammatory conditions
Spatial and developmental heterogeneity of calcium signalling in olfactory ensheathing cells

Olfactory ensheathing cells (OECs) are specialized glial cells in the mammalian olfactory system supporting growth of axons from the olfactory epithelium into the olfactory bulb. OECs in the olfactory bulb can be subdivided into OECs of the outer nerve layer and the inner nerve layer according to the expression of marker proteins and their location in the nerve layer. In the present study, we have used confocal calcium imaging of OECs in acute mouse brain slices and olfactory bulbs in toto to investigate physiological differences between OEC subpopulations. OECs in the outer nerve layer, but not the inner nerve layer, responded to glutamate, ATP, serotonin, dopamine, carbachol, and phenylephrine with increases in the cytosolic calcium concentration. The calcium responses consisted of a transient and a tonic component, the latter being mediated by store-operated calcium entry. Calcium measurements in OECs during the first three postnatal weeks revealed a downregulation of mGluR1 and P2Y1 receptor-mediated calcium signaling within the first 2 weeks, suggesting that the expression of these receptors is developmentally controlled. In addition, electrical stimulation of sensory axons evoked calcium signaling via mGluR1 and P2Y1 only in outer nerve layer OECs. Downregulation of the receptor-mediated calcium responses in postnatal animals is reflected by a decrease in amplitude of stimulation-evoked calcium transients in OECs from postnatal days 3 to 21. In summary, the results presented reveal striking differences in receptor responses during development and in axon-OEC communication between the two subpopulations of OECs in the olfactory bulb. 頲012 Wiley Periodicals, Inc.Full Tex
The adult spinal cord harbors a population of GFAP-positive progenitors with limited self-renewal potential

Adult neural stem cells (aNSCs) of the forebrain are GFAP-expressing cells that are intercalated within ependymal cells of the subventricular zone (SVZ). Cells showing NSCs characteristics in vitro can also be isolated from the periaqueductal region in the adult spinal cord (SC), but contradicting results exist concerning their glial versus ependymal identity. We used an induci- ble transgenic mouse line (hGFAP-CreERT2) to conditionally label GFAP-expressing cells in the adult SVZ and SC periaque- duct, and directly and systematically compared their self-renewal and multipotential properties in vitro. We demonstrate that a population of GFAP1 cells that share the morphology and the antigenic properties of SVZ-NSCs mostly reside in the dorsal aspect of the central canal (CC) throughout the spinal cord. These cells are non-proliferative in the intact spinal cord, but incorporate the S-phase marker EdU following spinal cord injury. Multipotent, clonal YFP-expressing neurospheres (i.e., deriv- ing from recombined GFAP-expressing cells) were successfully obtained from both the intact and injured spinal cord. These spheres however showed limited self-renewal properties when compared with SVZ-neurospheres, even after spinal cord injury. Altogether, these results demonstrate that significant differences exist in NSCs lineages between neurogenic and non- neurogenic regions of the adult CNS. Thus, although we confirm that a population of multipotent GFAP1 cells co-exists alongside with multipotent ependymal cells within the adult SC, we identify these cells as multipotent progenitors showing limited self-renewal properties
Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation.

The monocarboxylate transporter MCT4 is a high capacity carrier important for lactate release from highly glycolytic cells. In the central nervous system, MCT4 is predominantly expressed by astrocytes. Surprisingly, MCT4 expression in cultured astrocytes is low, suggesting that a physiological characteristic, not met in culture conditions, is necessary. Here we demonstrate that reducing oxygen concentration from 21% to either 1 or 0% restored in a concentration-dependent manner the expression of MCT4 at the mRNA and protein levels in cultured astrocytes. This effect was specific for MCT4 since the expression of MCT1, the other astrocytic monocarboxylate transporter present in vitro, was not altered in such conditions. MCT4 expression was shown to be controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α) since under low oxygen levels, transfecting astrocyte cultures with a siRNA targeting HIF-1α largely prevented MCT4 induction. Moreover, the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced MCT4 expression in astrocytes cultured in presence of 21% oxygen. In parallel, glycolytic activity was enhanced by exposure to 1% oxygen as demonstrated by the increased lactate release, an effect dependent on MCT4 expression. Finally, MCT4 expression was found to be necessary for astrocyte survival when exposed for a prolonged period to 1% oxygen. These data suggest that a major determinant of astrocyte MCT4 expression in vivo is likely the oxygen tension. This could be relevant in areas of high neuronal activity and oxygen consumption, favouring astrocytic lactate supply to neurons. Moreover, it could also play an important role for neuronal recovery after an ischemic episode
Age-Related Changes in Astrocytic and Ependymal Cells of the Subventricular Zone

Neurogenesis persists in the adult subventricular zone (SVZ) of the mammalian brain. During aging, the SVZ neurogenic capacity undergoes a progressive decline, which is attributed to a decrease in the population of neural stem cells (NSCs). However, the behavior of the NSCs that remain in the aged brain is not fully understood. Here we performed a comparative ultrastructural study of the SVZ niche of 2-month-old and 24-month-old male C57BL/6 mice, focusing on the NSC population. Using thymidine-labeling, we showed that residual NSCs in the aged SVZ divide less frequently than those in young mice. We also provided evidence that ependymal cells are not newly generated during senescence, as others studies suggest. Remarkably, both astrocytes and ependymal cells accumulated a high number of intermediate filaments and dense bodies during aging, resembling reactive cells. A better understanding of the changes occurring in the neurogenic niche during aging will allow us to develop new strategies for fighting neurological disorders linked to senescence