Browsing by Subject "Astrocytes"
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Item Open Access Association between cell-mediated demyelination and astrocyte stimulation.(Prog Brain Res, 1992) Smith, ME; Sommer, MAItem Open Access Astrocytes refine cortical connectivity at dendritic spines.(Elife, 2014-12-17) Risher, WC; Patel, S; Kim, IH; Uezu, A; Bhagat, S; Wilton, DK; Pilaz, L; Singh Alvarado, J; Calhan, OY; Silver, DL; Stevens, B; Calakos, N; Soderling, SH; Eroglu, CDuring cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.Item Open Access Astrocytes: Orchestrating synaptic plasticity?(Neuroscience, 2016-05) De Pittà, M; Brunel, N; Volterra, ASynaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes.Item Open Access Dectin-1 Signaling in Central Nervous System Autoimmunity(2022) Deerhake, Marion ElizabethDectin-1 is a C-type lectin receptor with diverse functions in orchestrating the innate immune response. Previous studies have primarily focused on the function of Dectin-1 in the setting of fungal infection. However, emerging evidence supports an important role for Dectin-1 in the context of autoimmunity and sterile inflammation. In this thesis, I investigated the function of Dectin-1 in central nervous system (CNS) autoimmunity. Specifically, I studied the role of Dectin-1 signaling in experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). Genetically modified mouse lines and immunophenotyping approaches were used to study Dectin-1 function in EAE. In addition, ex vivo studies using small molecule inhibitors and next-generation sequencing were used to perform in-depth characterization of Dectin-1 signaling mechanisms. Here I report that Dectin-1 limited EAE, while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, I found that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. This thesis research reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.
Item Open Access Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study.(Neural plasticity, 2016-01) De Pittà, Maurizio; Brunel, NicolasGlutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol.Item Open Access Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.(J Neurosci, 2004-05-12) Xu, Mei; Petraschka, Michael; McLaughlin, Jay P; Westenbroek, Ruth E; Caron, Marc G; Lefkowitz, Robert J; Czyzyk, Traci A; Pintar, John E; Terman, Gregory W; Chavkin, CharlesRelease of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.Item Open Access Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.(Nature, 2013-05) Benner, Eric J; Luciano, Dominic; Jo, Rebecca; Abdi, Khadar; Paez-Gonzalez, Patricia; Sheng, Huaxin; Warner, David S; Liu, Chunlei; Eroglu, Cagla; Kuo, Chay TPostnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ; also called subependymal zone) generate doublecortin (Dcx)(+) neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing the neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear whether there are conditions that favour astrogenesis over neurogenesis in the SVZ niche, and whether astrocytes produced there have different properties compared with astrocytes produced elsewhere in the brain. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical injury initiates a marked increase in Thbs4(hi) astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER(tm)4 lineage tracing demonstrated that it is these SVZ-generated Thbs4(hi) astrocytes, and not Dcx(+) neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4(KO/KO)) showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing cells expressing Dcx migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular haemorrhage into the brain parenchyma of Thbs4(KO/KO) mice. Taken together, these findings have important implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles.Item Open Access Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity.(eLife, 2019-11-04) Battaglia, Rachel A; Beltran, Adriana S; Delic, Samed; Dumitru, Raluca; Robinson, Jasmine A; Kabiraj, Parijat; Herring, Laura E; Madden, Victoria J; Ravinder, Namritha; Willems, Erik; Newman, Rhonda A; Quinlan, Roy A; Goldman, James E; Perng, Ming-Der; Inagaki, Masaki; Snider, Natasha TAlexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.Item Open Access Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.(Nature, 2012-02-15) Koivunen, Peppi; Lee, Sungwoo; Duncan, Christopher G; Lopez, Giselle; Lu, Gang; Ramkissoon, Shakti; Losman, Julie A; Joensuu, Päivi; Bergmann, Ulrich; Gross, Stefan; Travins, Jeremy; Weiss, Samuel; Looper, Ryan; Ligon, Keith L; Verhaak, Roel GW; Yan, Hai; Kaelin, William GThe identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy.