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Acute Cannabinoid Treatment 'in vivo' Causes an Astroglial CB1R-Dependent LTD At Excitatory CA3-CA1 Synapses Involving NMDARs and Protein SynthesisKesner, Philip 19 November 2012 (has links)
Cannabinoids have been shown to alter synaptic plasticity but the mechanism by which
this occurs at hippocampal CA3-CA1 synapses in vivo is not yet known. Utilizing in vivo
electrophysiological recordings of field excitatory postsynaptic potentials (fEPSP) on
anesthetized rats and mice as well as three lines of conditional knockout mouse models,
the objective was to show a two-part mechanistic breakdown of cannabinoid-evoked
CA3-CA1 long-term depression (LTD) in its induction as well as early and later-phase
expression stages. It was determined that this cannabinoid-induced in vivo LTD requires
cannabinoid type-1 receptors (CB1Rs) on astrocytes, but not CB1Rs on glutamatergic or
GABAergic neuronal axons/terminals. Pharmacological testing determined that
cannabinoid-induced in vivo LTD also requires activation of NMDA receptors (NMDAR)
and subsequent postsynaptic endocytosis of AMPA receptors (AMPAR). There exists a
clear role for NR2B-containing NMDARs in a persistent, transitory form, potentially
related to prolonged or delayed glutamate release (possibly as a result of the astrocytic
network). A key determination of the expression phase is the involvement of new protein synthesis (using translation and transcription inhibitors) – further evidence of the long-term action of the synaptic plasticity from a single cannabinoid dose.
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Intracellular Calcium Dynamics In Dendrites Of Hippocampal Neurons Rendered Epileptic And In Processes Of Astrocytes Following Glutamate PretreatmentPadmashri, R 08 1900 (has links)
The fundamental attribute of neurons is their cellular electrical excitability, which is based on the expression of a plethora of ligand- and voltage-gated membrane channels that give rise to prominent membrane currents and membrane potential variations that represent the biophysical substrate underlying the transfer and integration of information
at the cellular level. Dendrites have both an electrical and a biochemical character, which are closely linked. In contrast, glial cells are non-electrically excitable but nevertheless display a form of excitability that is based on variations of the Ca2+ concentration in the cytosol rather than electrical changes in the membrane. Cytoplasmic Ca2+ serves as an
intracellular signal that is responsible for controlling a multitude of cellular processes. The key to this pleiotropic role is the complex spatiotemporal organization of the [Ca2+]i rise evoked by extracellular agonists, which allows selected effectors to be recruited and specific actions to be initiated. Ca2+ handling in the cell is maintained by operation of multiple mechanisms of Ca2+ influx, internal release, diffusion, buffering and extrusion. Ca2+ tends to be a rather parochial operator with a small radius of action from its point of
entry at the cytoplasm resulting in the concept of microdomains. Dendritic Ca2+ signaling have been shown to be highly compartmentalized and astrocytic processes have been reported to be constituted by hundreds of microdomains that represent the elementary units of the astrocyte Ca2+ signal, from where it can eventually propagate to other regions of the cell. The astrocyte Ca2+ elevation may thus act as intra and intercellular signal that can propagate within and between astrocytes, signaling to different regions of the cell and to different cells. The spatio-temporal features of neuron-to-astrocyte communication, results from diverse neurotransmitters and signaling pathways that converge and cooperate to shape the Ca2+ signal in astrocytes. Alterations in Ca2+ homeostasis have been shown to be associated with major pathological conditions of the brain such as epilepsy, ischemia and neurodegenerative diseases.
Although there are evidences of Ca2+ rise in hippocampal neurons in in vitro models of
epilepsy (Pal et al., 1999; Limbrick et al., 2001), there is no information on the Ca2+
regulatory mechanisms operating in discrete compartments of the epileptic neuron
following Ca2+ influx through voltage gated calcium channels (VGCCs). In the first part
of the work, the spatial and temporal profiles of depolarization induced changes in the intracellular Ca2+ concentration in the dendrites of cultured autaptic hippocampal pyramidal neurons rendered epileptic experimentally have been addressed. Our in vitro epilepsy model consisted of hippocampal neurons in autaptic culture that were grown in the presence of kynurenate and high Mg2+, and subsequently washing the preparation free of the blockers. To understand the differences in Ca2+ handling mechanisms in different
compartments of a control neuron and the kynurenate treated neuron, a combination of
whole-cell patch-clamp recording and fast Ca2+ imaging methods using the Ca2+ indicator
Oregon Green 488 BAPTA-1 was applied. All our analysis was focused on localized regions in the dendrite that showed pronounced Ca2+ transients upon activation of high voltage activated (HVA) Ca2+ channels. The spatial extent of Ca2+ signals suggested the presence of distinct dendritic compartments that respond to the depolarizing stimulus. Further, the local Ca2+ transients were observed even in the presence of NMDA and AMPA receptor antagonists, suggesting that the opening of VGCCs primarily triggered the local Ca2+ changes. The prominent changes in intracellular Ca2+ observed in these
dendritic regions appear to be sites where Ca2+ evoked dendritic exocytosis (CEDE) takes
place. Since cellular Ca2+ buffers determine the amplitude and diffusional spread of
neuronal Ca2+ signals, quantitative estimates of the time-dependent spread of intracellular Ca2+ in the dendritic compartments in the control and treated neurons were done using image processing techniques. Physiological changes in Ca2+ channel functioning were also induced by kynurenate treatment and one such noticeable difference was the observation of Ca2+ dependent inactivation in the treated neurons. We provide evidences of localized Ca2+ changes in the dendrites of hippocampal neurons that are rendered epileptic by kynurenate treatment, suggesting that these sites are more vulnerable (Padmashri et al., 2006). This might contribute to the epileptiform activity by local changes in cellular and membrane properties in complex ways that remains to be clearly understood.
Status Epilepticus (SE), stroke and traumatic brain injury are all associated with large increases in extracellular glutamate concentrations. The concentration of glutamate in the extracellular fluid is around 3-4 µM and astrocytes are primarily responsible for the uptake of glutamate at the synapses. The extracellular levels of glutamate has been shown to increase dramatically (16 fold) in human SE suggesting an important role of glutamate
in the mechanism of seizure activity and seizure related brain damage (Carlson et al.,
1992). Several other studies have also shown a persistent increase in extracellular
glutamate concentration to potentially neurotoxic concentrations in the epileptogenic hippocampus (During and Spencer, 1993; Sherwin, 1999; Cavus et al., 2005).
We addressed the problem related to the effects of prolonged glutamate pretreatment on Ca2+ signaling in an individual astrocyte and its adjoining astrocyte (astrocyte pair),
rather than on a syncytium of astrocytes in culture. Individual astrocytes may have
functional domains that respond to an agonist through distinct receptor signaling systems. These are difficult to observe in studies that are done on glial syncytium because of spatial limits of image capture. This was examined with simultaneous somatic patch-pipette recording of a single astrocyte to evoke voltage-gated calcium currents, and Ca2+ imaging using the Ca2+ indicator Oregon Green 488 BAPTA-1 to identify the Ca2+ microdomains. Transient Ca2+ changes locked to the depolarization were observed in certain compartments in the astrocyte processes of the depolarized astrocyte and the responses were more pronounced in the adjoining astrocyte of the astrocyte pair. The Ca2+ transient amplitudes were enhanced on pretreatment of cells with glutamate (500 µM for 20 minutes). Estimation of local Ca2+ diffusion coefficients in the astrocytic processes indicated higher values in the adjoining astrocyte of the glutamate pretreated
group. In order to understand the underlying mechanisms, we performed the experiments
in the presence of different blockers for the metabotropic glutamate receptor, inositol
1,4,5 triphosphate (IP3) receptors and gap junctions. Ca2+ transients recorded on
pretreatment of cells with glutamate showed attenuated responses in the presence of the
metabotropic glutamate receptor (mGluR) antagonist α-Methyl(4-Carboxy-Phenyl)
Glycine (MCPG). Intracellular heparin (an antagonist of IP3 receptor) introduced in the
depolarized astrocyte did not affect the Ca2+ transients in the heparin loaded astrocyte, but attenuated the [Ca2+]i responses in the adjoining astrocyte suggesting that IP3 may be the transfer signal. The uncoupling agent 1-Octanol attenuated the [Ca2+]i responses in
the adjoining cell of the astrocyte pair in both the control and glutamate pretreated
astrocytes indicating the role of gap junctional communication. The findings of [Ca2+]i responses within discrete regions of astrocytic processes suggest that astrocytes may be comprised of microdomains whose properties are altered by glutamate pretreatment. The data also indicates that glutamate induced alterations in Ca2+ signaling in the astrocyte pair may be mediated through phospholipase C (PLC), IP3, internal Ca2+ stores, VGCCs and gap junction channels (Padmashri and Sikdar, 2006).
Neuronal (EAAC-1) and glial (GLT-1 and GLAST) glutamate transporters facilitate
glutamate reuptake after synaptic release. Transgenic mice with GLT-1 knockout display
spontaneous epileptic activity (Tanaka et al., 1997) and loss of glial glutamate
transporters using chronic antisense nucleotide administration was reported to result in elevated extracellular glutamate levels and neurodegeneration characteristic of excitotoxity (Rothstein et al., 1996). Dysfunction of glutamate transporters and the
resulting increase of glutamate have been speculated to play an important role in infantile epilepsies (Demarque et al., 2004). We examined the effects of pretreatment with glutamate in the presence of the glutamate transport inhibitor threo-β-hydroxy-aspartate (TBHA) and in Na+-free extracellular medium to understand whether this resulted in any alteration in the astrocytic intracellular Ca2+ dynamics following activation of voltage gated calcium channels. The Ca2+ responses were found to be attenuated in both the cases
indicating that the elevated levels of extracellular glutamate due to blockade of glutamate transporters may influence the responses mediated by the astrocytic glutamate receptors. Our studies indicate that the heightened extracellular glutamate concentration is not gliotoxic in our experimental system, although it may have a profound effect on altering the activity of surrounding neurons which was not addressed in the present work.
Several studies have indicated that neurons control the level of gap junction mediated
communication between astrocytes (Giaume and McCarthy, 1996; Rouach et al, 2000). All our earlier studies were done on process bearing astrocytes that were co-cultured with
neurons. We have addressed the question as to whether the spatio-temporal changes in
[Ca2+]i in astrocyte pairs differ if the astrocytes are cultured in the absence of neurons. The results indicate that there is indeed a significant reduction in the responses that are evoked in response to the depolarization pulse in the adjoining cell of the astrocyte pair. These experiments demonstrate that neurons in the cocultures may selectively enhance the Ca2+ responses possibly by increasing the coupling between the two cells.
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Caractérisation spatiale des syncytia formés par le couplage des astrocytes du noyau sensoriel principal du nerf trijumeau en fonction de la concentration de calcium extracellulaire.Lavoie, Raphaël 01 1900 (has links)
Le mouvement masticatoire est généré et coordonné par un générateur de patron central (GPC) situé au niveau du pont. Plusieurs résultats antérieurs de notre laboratoire soutiennent que le réseau de neurones à l’origine de la rythmogénèse est situé dans le noyau sensoriel principal du nerf trijumeau (NVsnpr). Ces mêmes expériences révèlent que des diminutions de la concentration calcique extracellulaire ([Ca2+]e) tiennent une place importante dans la génération des bouffées de décharges des neurones de cette région. Notre laboratoire tente de vérifier si la contribution des astrocytes à l’homéostasie de la concentration calcique extracellulaire est impliquée dans la genèse du rythme. Cette étude a pour but la caractérisation spatiale du syncytium astrocytaire au sein du NVsnpr dorsal et l’étude de l’effet de la [Ca2+]e sur les propriétés astrocytaires électrophysiologiques et de connectivité. Nous avons utilisés pour ce faire la technique d’enregistrement par patch-clamp sur une préparation en tranche de tronc cérébral de rat. Nous démontrons ici que la diminution de la [Ca2+]e n’affecte pas les propriétés électrophysiologiques astrocytaires, mais induit une augmentation de la taille du syncytium. De plus, nous établissons l’existence au sein du NVsnpr dorsal d’une organisation anatomofonctionnelle du réseau astrocytaire calquée sur l’organisation neuronale. / The masticatory movement is generated and coordinated by a central pattern generator (CPG) located in the pons. Previous results from our laboratory suggest that the neural network responsible for its rythmogenesis is located in the trigeminal main sensory nucleus (NVsnpr). Moreover, results indicate that in this region, decrease in extracellular calcium concentration ([Ca2+]e) plays an important role in genarating burst. One of our laboratory's goal is to assess if the contribution of astrocytes to the extracellular calcium concentration homeostasis is involved in the genesis of the mastication rhythm. With this study, we characterized the astrocyte syncytium within the NVsnpr and measured the effect of [Ca2+]e on the astrocytes electrophysiology and their networks. A patch-clamp recording technique in conjunction with a rat brain stem slice preparation was used. We demonstrate that a decrease in [Ca2+]e does not affect the electrophysiological properties of astrocytes but induces an increase in the size of the syncytium. We also report the existence, within the dorsal NVsnpr, of an anatomofunctional organization between neurons and astrocytes.
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Altération du couplage neurovasculaire par l'angiotensine II : évaluation du rôle de la signalisation calcique astrocytaireBoily, Michaël 07 1900 (has links)
No description available.
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Caractérisation spatiale des syncytia formés par le couplage des astrocytes du noyau sensoriel principal du nerf trijumeau en fonction de la concentration de calcium extracellulaireLavoie, Raphaël 01 1900 (has links)
No description available.
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Localised dosing and nanodetection using a novel scanning ion conductance microscope and its application to Alzheimer's diseaseChen, Wei-Hsin Chen January 2018 (has links)
Scanning ion conductance microscopy (SICM) is a technique for non-contact topographic imaging. In this thesis, a biophysical investigation into Alzheimer's Disease (AD) was carried, with toxic oligomers dosed locally and quantitatively on to single astrocytes using SICM and simultaneously monitoring the response of the target cell. Examination of the effectiveness of antibodies that bind to Abeta or alpha-synuclein (Asyn)peptides depends on the measurement of oligomer-induced abnormal calcium homeostasis in single astrocytes. The method was shown to work at physiological concentrations of oligomers. A series of experiments measuring the reduction in calcium inux in mixtures of antibodies and cerebrospinal fluid (CSF) of AD patients suggested that the binding to co-oligomers composed of Abeta and Asyn may be crucial in the treatment of AD. Furthermore, it may be beneficial to test antibodies before the clinical trial using this assay. The mechanism of this entry of calcium is hypothesised to be the result of the formation of oligomer-induced transient pores in the cell membrane. To verify this hypothesis, a new SICM instrument was built with two nanopipettes; one for dosing and one for detection of the adenosine triphosphate (ATP) release from these pores. A variety of different ATP sensors were made. The best had a sensitivity of 10 micro molar and works as a hexokinase-cofunctioned electrolyte-gated organic field-effect-transistor. However no statistically significant results for ATP release have been obtained in the experiments performed to date. Overall this thesis describes new biophysical methods to study the effect of protein aggregates on live cells and the effectiveness of potential therapies, such as antibodies and nanobodies, to reduce these aggregate induced effects. It can be applied to synthetic aggregates of Abeta or the aggregates present in human CSF.
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Modelagem computacional de redes genéticas regulatórias / Computational modelling of gene regulatory networksGupta, Shantanu 30 September 2016 (has links)
In biology, regulatory networks are sets of macromolecules, mostly proteins and
RNAs that interact to execute task. The main players in regulatory networks are DNAbinding
proteins, also called transcription factors as they modulate the first step in gene
expression. A gene regulatory network (GRN) is a set of genes or proteins that interact with
each other to control a specific cell function. Gene regulatory networks are important in
development, differentiation and to respond to environmental cues. Gene regulatory
networks (GRNs) are the on-off switches of a cell operating at the gene and/or protein
level. The modeling methods can be broadly categorized into continuous and discrete. In
this work , we dedicate attention to discrete models on cell senescence models for
Astrocyte [35], the modelling of drug synergies to control gastric cancer [38], and we also
wrote a paper about Discrete and Continuous Model, advantage or disadvantage of these
models and a list of available softwares for using these kind of approaches. / Em biologia, redes regulatórias são conjuntos de macromoléculas,
principalmente proteínas e RNAs que interagem para executar uma tarefa. As proteínas
de ligação de DNA, também chamadas de fatores de transcrição, são as principais
executoras nas redes regulatórias, visto que modulam o primeiro passo na expressão
gênica. Uma rede genética regulatória (RRG) é um conjunto de genes ou proteínas que
interagem uns com os outros para controlar uma função celular específica. Redes
regulatórias são importantes no desenvolvimento, diferenciação e para responder aos
sinais ambientais. Elas são os botões de liga/desliga de uma célula operando no nível do
gene e/ou proteína. Seus métodos de modelagem podem ser geralmente classificados
em contínuos e discretos. Neste trabalho, dedicamos atenção aos modelos discretos em
senescência celular para astrócitos [35], a modelagem de sinergias de drogas para
controle do câncer gástrico [38] e também escrevemos um artigo sobre Modelos
Discretos e Contínuos, vantagens e desvantagens desses modelos e listagem dos
softwares disponíveis para uso nesse tipo de abordagem.
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Açaí (Euterpe oleracea Mart.) como importante fonte de alguns elementos químicos essenciais potencialmente biodisponíveis e efeito neuroprotetor de seu extrato frente à neurotoxicidade do Manganês em astrócitos / Açaí (Euterpe oleracea Mart.) as an important source of potentially bioavailable essential chemical elements and neuroprotective effect of its extract on Manganese induced neurotoxicity in astrocytesVívian da Silva Santos 21 January 2014 (has links)
O açaí é uma fruta da amazônia brasileira de consumo emergente no Brasil e outras regiões do mundo. Primordialmente consumida na sua forma de polpa e estabelecida como uma \"superfruta\" graças ao seu potencial antioxidante e anti-inflamatório. No entanto, pouco se sabe sobre sua composição em relação aos elementos químicos essenciais. No presente estudo, a análise sistemática de 12 polpas produzidas com frutos de diferentes localidades demonstrou que a polpa de açaí é naturalmente rica nos elementos Ca, Cu, Fe, Mg, Zn, com destaque para as concentrações encontradas de Mn que foram notoriamente maiores do que as comumente observadas em alimentos considerados como fonte principal deste elemento químico essencial na dieta. Cabe destacar que em valores médios, todos os elementos químicos estudados no açaí apresentaram-se em concentrações que contribuem significativamente para as suas necessidades diárias preconizadas. Entretanto, a análise do fracionamento químico da polpa de açaí demonstrou que o ferro está em uma forma potencialmente indisponível; enquanto que cerca de 40% dos elementos cálcio, magnésio, manganês e zinco estão quelados a um composto não fenólico de alta solubilidade em água e que pode aumentar suas biodisponibilidades. Diferentemente dos demais, o cobre interagiu significativamente com a fração fenólica solúvel em água do alimento. A fração fenólica eluída com metanol por SPE demonstrou ter considerável atividade antioxidante direta no ensaio de sequestro de DPPH com EC50 de 19,1 ?g/L e foi eficaz na atenuação da citotoxicidade, estresse oxidativo e alteração funcional induzidos por 500 ?M de MnCl2 em cultura primária de astrócitos, avaliados pelos ensaios de LDH e MTT, GSH/GSSG, F2-IsoPs, captação de glutamato e expressão de Nrf2. Este extrato de açaí em uma concentração ótima de 0,1 ?g/mL preveniu o estresse oxidativo induzido por Mn restaurando a razão GSH/GSSG, protegendo as membranas astrocitárias da lipoperoxidação e diminuindo a expressão de Nrf2. Uma concentração mais elevada de extrato de açaí exacerbou os efeitos do Mn nestes mesmos parâmetros, exceto na lipoperoxidação medida pela formação de F2-IsoPs. Assim, o pré-tratamento dos astrócitos com concentrações mais elevadas destas antocianinas com exposição ao Mn em sequência, pode predispor os astrócitos fazendo com que um efeito pró-oxidante prevaleça. Estes achados devem ser considerados em estudos futuros que explorem a potencialidade das antocianinas do açaí em formulações nutracêuticas para obtenção de efeitos antioxidantes e neuroprotetores ideais. Assim, conclui-se que o próprio açaí possui uma fração de compostos fenólicos capaz de atenuar os efeitos oxidativos do Mn e que portanto, pode indicar uma segurança alimentar do consumo do fruto em quantidades moderadas. / Açaí is a fruit from Brazilian Amazon with an exotic flavor possessing high antioxidant and anti-inflammatory properties. Based on these properties, the fruit is classified as one of the new \"super fruits\". However, few is known about its essential chemical elements content. In this study, the systematic analysis of 12 freeze-dried pulps processed with açaí of different locations showed that açaí pulp is naturally rich in Ca, Cu, Fe, Mg, Zn, and especially amounts of Mn, which was significantly greater than in foods considered Mn dietary source, were found. In average values, all determined essential chemical elements contribute significantly to their recommended daily intake requirements. However, fractionation analysis of açai showed that iron is potentially not bioavailable. While about 40% of calcium, magnesium, manganese, and zinc are binding to a non-phenolic compound high soluble in water, which may increase their bioavailabilities. Copper is significantly bound to water-soluble phenolic fraction in açaí. This phenolic fraction eluted with methanol by SPE provided considerable direct antioxidant activity on the DPPH scavenging assay with EC50 of 19.1 ?g/L and was effective attenuating cytotoxicity, oxidative stress, and functional alterations induced by 500 ?M of MnCl2 in primary cultured astrocytes, which was assessed by MTT and LDH assay, GSH/GSSG ratio, F2-IsoPs formation, glutamate uptake, and Nrf2 levels. This anthocyanin-rich açaí extract in an optimal concentration of 0.1 ?g/mL prevented oxidative stress induced by Mn restoring the GSH/GSSG ratio, protecting the astrocytic membrane from lipid peroxidation and decreasing levels of Nrf2. A higher concentration of the same açaí extract exacerbated the effects of Mn in these same parameters, except on lipid peroxidation assessed by F2-IsoPs. In constrast, pre-treating with high concentrations of açaí\'s anthocyanins followed by Mn exposure, pro-oxidant effects likely prevails. These findings should be considered in future studies regarding the potential of anthocyanins in açaí on nutraceutical formulations to obtain optimal antioxidant and neuroprotective effects. Thus, we conclude that the own açaí has a phenolic fraction capable of attenuates the oxidative effects of Mn. So, may indicates that moderate açaí consumption is dietary safe regarding Mn neurotoxicity.
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Alpha-Synuclein Oligomers : Cellular Mechanisms and Aspects of Antibody TreatmentGustafsson, Gabriel January 2017 (has links)
In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), aggregated α-synuclein deposit inside cells within the brain. Smaller soluble α-synuclein aggregates, oligomers, are present both intra- and extracellularly. The α-synuclein oligomers are known to be particularly harmful, although the underlying neurotoxic mechanisms are not fully understood. The aim of this thesis was to investigate the pathogenic roles of α-synuclein oligomers and the possibility to target such species with antibody treatment. Passive immunotherapy with α-synuclein antibodies can lead to reduced pathology and ameliorated symptoms in transgenic mice. However, it remains unknown whether the antibodies are taken up by cells or whether they act extracellularly. In Paper I, we assessed cellular internalization of various α-synuclein monoclonal antibodies. The oligomer selective mAb47 displayed the highest uptake, which was promoted by the extracellular presence of α-synuclein. Alpha-synuclein aggregates can be found in both neurons and glial cells, but the pathogenic role of glial deposits has only been sparsely investigated. In Paper II, co-cultures of neurons and glia were exposed to α-synuclein oligomers. The astrocytes in the cultures rapidly accumulated oligomers, which were only partially degraded by lysosomes. The sustained intracellular α-synuclein deposits were associated with mitochondrial stress reactions in the astrocytes. In Paper III, we sought to explore whether the astrocytic pathology induced by α-synuclein oligomers could be ameliorated by antibody treatment. Pre-incubation of oligomers with mAb47 promoted α-synuclein clearance, reduced astrocytic accumulation and rescued cells from mitochondrial stress. We could demonstrate that binding of the antibody to its antigen in the extracellular space was crucial for these effects to occur. The progressive pathology in PD is believed to be driven by cell-to-cell spreading of α-synuclein aggregates, potentially via exosomes and other extracellular vesicles (EVs). In Paper IV, we found that either fusing α-synuclein to a non-physiological protein tag or introducing the PD-causing A53T mutation directed α-synuclein towards EV secretion. Also, EV-associated α-synuclein was particularly prone to induce toxicity in recipient cells. In conclusion, this thesis sheds new light on the cellular dysfunction related to α-synuclein pathology and on how the underlying pathogenic processes may be targeted by antibody treatment.
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Acute Cannabinoid Treatment 'in vivo' Causes an Astroglial CB1R-Dependent LTD At Excitatory CA3-CA1 Synapses Involving NMDARs and Protein SynthesisKesner, Philip January 2012 (has links)
Cannabinoids have been shown to alter synaptic plasticity but the mechanism by which
this occurs at hippocampal CA3-CA1 synapses in vivo is not yet known. Utilizing in vivo
electrophysiological recordings of field excitatory postsynaptic potentials (fEPSP) on
anesthetized rats and mice as well as three lines of conditional knockout mouse models,
the objective was to show a two-part mechanistic breakdown of cannabinoid-evoked
CA3-CA1 long-term depression (LTD) in its induction as well as early and later-phase
expression stages. It was determined that this cannabinoid-induced in vivo LTD requires
cannabinoid type-1 receptors (CB1Rs) on astrocytes, but not CB1Rs on glutamatergic or
GABAergic neuronal axons/terminals. Pharmacological testing determined that
cannabinoid-induced in vivo LTD also requires activation of NMDA receptors (NMDAR)
and subsequent postsynaptic endocytosis of AMPA receptors (AMPAR). There exists a
clear role for NR2B-containing NMDARs in a persistent, transitory form, potentially
related to prolonged or delayed glutamate release (possibly as a result of the astrocytic
network). A key determination of the expression phase is the involvement of new protein synthesis (using translation and transcription inhibitors) – further evidence of the long-term action of the synaptic plasticity from a single cannabinoid dose.
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