Sphingosine-1-phosphate (S1P) impacts presynaptic functions by regulating synapsin i localization in the presynaptic compartment

Growing evidence indicates that sphingosine-1-P (S1P) upregulates glutamate secretion in hippocampal neurons. However, the molecular mechanisms through which S1P enhances excitatory activity remain largely undefined. The aim of this study was to identify presynaptic targets of S1P action controlling exocytosis. Confocal analysis of rat hippocampal neurons showed that S1P applied at nanomolar concentration alters the distribution of Synapsin I (SynI), a presynaptic phosphoprotein that controls the availability of synaptic vesicles for exocytosis. S1P induced SynI relocation to extrasynaptic regions of mature neurons, as well as SynI dispersion from synaptic vesicle clusters present at axonal growth cones of developing neurons. S1P-induced SynI relocation occurred in a Ca2+- independent but ERK-dependent manner, likely through the activation of S1P3 receptors, as it was prevented by the S1P3 receptor selective antagonist CAY1044 and in neurons in which S1P3 receptor was silenced. Our recent evidence indicates that microvesicles (MVs) released by microglia enhance the metabolism of endogenous sphingolipids in neurons and stimulate excitatory transmission. We therefore investigated whether MVs affect SynI distribution and whether endogenous S1P could be involved in the process. Analysis of SynI immunoreactivity showed that exposure to microglial MVs induces SynI mobilization at presynaptic sites and growth cones, whereas the use of inhibitors of sphingolipid cascade identified S1P as the sphingolipid mediating SynI redistribution. Our data represent the first demonstration that S1P induces SynI mobilization from synapses, thereby indicating the phosphoprotein as a novel target through which S1P controls exocytosis. Significance Statement Growing evidence indicates that the bioactive lipid sphingosine and its metabolite sphingosine-1-P (S1P) stimulate excitatory transmission. While it has been recently clarified that sphingosine influences directly the exocytotic machinery by activating the synaptic vesicle protein VAMP2 to form SNARE fusion complexes, the molecular mechanism by which S1P promotes neurotransmission remained largely undefined. In this study, we identify Synapsin I, a presynaptic phosphoprotein involved in the control of availability of synaptic vesicles for exocytosis, as the key target of S1P action. In addition, we provide evidence that S1P can be produced at mature axon terminals as well as at immature growth cones in response to microglia-derived signals, which may be important to stabilize nascent synapses and to restore or potentiate transmission

Síndrome de Burnout em docentes: fatores de risco e métodos para prevenção

A Síndrome de Burnout tem se mostrado crescente, principalmente em profissionais da educação, onde diferentes causas têm sido remetidas ao surgimento da mesma, como carência de recursos, de suporte e pressões advindas da convivência interpessoal, gerando uma profissão de suma desenvoltura e estresse. O objetivo desse estudo é analisar através de uma revisão integrativa na literatura os principais fatores de riscos e estratégias para prevenção da SB em docentes. Trata-se de uma revisão integrativa da literatura proveniente da BVS com bases de dados da Scielo, LILACS e MEDLINE, através dos seguintes DeCS: Síndrome de Burnout”, “Docência” e “Fatores associados”, combinados entre si pelo operador booleano AND. Foram encontrados 128 estudos e selecionados 8 artigos para compor esta revisão. Os principais fatores associados a SB  descritas nos estudos foram as relações interpessoais, a falta de estrutura e ambiente adequados para o desenvolvimento do ensino, desinteresse por parte dos alunos, relação de desgaste com superiores e demais fatores como violência, assédio e questões relacionadas as necessidades humanas básicas, além de questões salariais, a desvalorização profissional e a alta jornada de trabalho. Os achados reforçam necessidade de aproximar políticas de saúde do trabalhador voltadas ao ambiente escolar/acadêmico, sobretudo na prevenção de causas de transtornos mentais relacionadas ao desenvolvimento da SB nesses profissionais

Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations

Recent evidence indicates synaptic dysfunction as an early mechanism affected in neuroinflammatory diseases, such as multiple sclerosis, which are characterized by chronic microglia activation. However, the mode(s) of action of reactive microglia in causing synaptic defects are not fully understood. In this study, we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Among them, miR-146a-5p, a microglia-specific miRNA not present in hippocampal neurons, controls the expression of presynaptic synaptotagmin1 (Syt1) and postsynaptic neuroligin1 (Nlg1), an adhesion protein which play a crucial role in dendritic spine formation and synaptic stability. Using a Renilla-based sensor, we provide formal proof that inflammatory EVs transfer their miR-146a-5p cargo to neuron. By western blot and immunofluorescence analysis we show that vesicular miR-146a-5p suppresses Syt1 and Nlg1 expression in receiving neurons. Microglia-to-neuron miR-146a-5p transfer and Syt1 and Nlg1 downregulation do not occur when EV\ue2\u80\u93neuron contact is inhibited by cloaking vesicular phosphatidylserine residues and when neurons are exposed to EVs either depleted of miR-146a-5p, produced by pro-regenerative microglia, or storing inactive miR-146a-5p, produced by cells transfected with an anti-miR-146a-5p. Morphological analysis reveals that prolonged exposure to inflammatory EVs leads to significant decrease in dendritic spine density in hippocampal neurons in vivo and in primary culture, which is rescued in vitro by transfection of a miR-insensitive Nlg1 form. Dendritic spine loss is accompanied by a decrease in the density and strength of excitatory synapses, as indicated by reduced mEPSC frequency and amplitude. These findings link inflammatory microglia and enhanced EV production to loss of excitatory synapses, uncovering a previously unrecognized role for microglia-enriched miRNAs, released in association to EVs, in silencing of key synaptic genes

Active endocannabinoids are secreted on extracellular membrane vesicles

Endocannabinoids primarily influence neuronal synaptic communication within the nervous system. To exert their function, endocannabinoids need to travel across the intercellular space. However, how hydrophobic endocannabinoids cross cell membranes and move extracellularly remains an unresolved problem. Here, we show that endocannabinoids are secreted through extracellular membrane vesicles produced by microglial cells. We demonstrate that microglial extracellular vesicles carry on their surface N-arachidonoylethanolamine (AEA), which is able to stimulate type-1 cannabinoid receptors (CB1), and inhibit presynaptic transmission, in target GABAergic neurons. This is the first demonstration of a functional role of extracellular vesicular transport of endocannabinoids

Metis coronagraph - Flight Model under acceptance tests

METIS, an inverted-occultation coronagraph, is one of the most relevant remote sensing instruments of the Solar Orbiter mission of the European Space Agency (ESA). METIS is the only coronagraph ever designed to acquire simultaneous images of the solar corona in two different wavelengths (visible light between 580 nm and 640 nm, and the Lyman- line of Hydrogen at 121.6 nm). The visible channel also includes a polarimeter to observe the linearly polarized component of the K corona. The Qualication Reviews of the coronagraph under responsibility of the Italian industries OHB-I and TAS-I and of the visible and ultraviolet light detector assemblies (VLDA and ULDA) developed by the Max Planck Institute for Solar System Research in Goettingen, Germany, were successfully concluded in 2016. The main optics, in particular the mirrors that are under the responsibility of the Astronomical Institute of the Academy of Sciences of the Czech Republic are also qualied at sub-system level. The main elements (UVDA, VLDA, Mirrors, Polarimeter, etc.) are nally integrated in the coronagraph along with the Processing and Power Unit, High Voltage Unit and Camera Power Converter in the TAS-I facility in Turin. The entrance of the telescope is equipped with sealing protection cap, designed under the responsibility of the Spanish company SENER to be compliant with the very stringent and challenging contamination requirements and to be ejected once in orbit. The vibrations and thermal-vacuum acceptance tests for the Flight Model of the integrated system are successfully completed. After the EMC acceptance tests, the activities of verification and calibration of the instrument will be carried out by the METIS Industrial and Scientific Team under the responsibility of the Principal Investigator, Prof. E. Antonucci

Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism

Microvesicles (MVs) released into the brain microenvironment are emerging as a novel way of cell-to-cell communication. We have recently shown that microglia, the immune cells of the brain, shed MVs upon activation but their possible role in microglia-to-neuron communication has never been explored. To investigate whether MVs affect neurotransmission, we analysed spontaneous release of glutamate in neurons exposed to MVs and found a dose-dependent increase in miniature excitatory postsynaptic current (mEPSC) frequency without changes in mEPSC amplitude. Paired-pulse recording analysis of evoked neurotransmission showed that MVs mainly act at the presynaptic site, by increasing release probability. In line with the enhancement of excitatory transmission in vitro, injection of MVs into the rat visual cortex caused an acute increase in the amplitude of field potentials evoked by visual stimuli. Stimulation of synaptic activity occurred via enhanced sphingolipid metabolism. Indeed, MVs promoted ceramide and sphingosine production in neurons, while the increase of excitatory transmission induced by MVs was prevented by pharmacological or genetic inhibition of sphingosine synthesis. These data identify microglia-derived MVs as a new mechanism by which microglia influence synaptic activity and highlight the involvement of neuronal sphingosine in this microglia-to-neuron signalling pathway