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Depression is a disabling and highly prevalent psychiatric illness. Multiple studies have linked glutamatergic dysfunction with the pathophysiology of depression, but the exact alterations in the glutamatergic system that contribute to depressive-like behaviors are not fully understood. Recent evidence suggests that a decreased level in neuronal glutamate transporter (EAAT3), known to control glutamate levels and limit the activation of glutamate receptors at synaptic sites, may contribute to the manifestation of a depressive phenotype. Here, we tested the possibility that increased EAAT3 expression at excitatory synapses could reduce the susceptibility of mice to develop depressive-like behaviors when challenged to a 5-week unpredictable chronic mild stress (UCMS) protocol. Mice overexpressing EAAT3 in the forebrain (EAAT3glo/CMKII) and control littermates (EAAT3glo) were assessed for depressive-like behaviors and long-term memory performance after being subjected to UCMS conditions. We found that, after UCMS, EAAT3glo/CMKII mice did not exhibit depressive-like behaviors or memory alterations observed in control mice. Moreover, we found that EAAT3glo/CMKII mice did not show alterations in phasic dopamine release in the nucleus accumbens neither in long-term synaptic plasticity in the CA1 region of the hippocampus after UCMS, as observed in control littermates. Altogether these results suggest that forebrain EAAT3 overexpression may be related to a resilient phenotype, both at behavioral and functional level, to the deleterious effect of chronic stress, highlighting the importance of neuronal EAAT3 in the pathophysiology of depressive-like behaviors.

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Aim: To review the main pathological findings of Neuromyelitis Optica Spectrum Disorder (NMOSD) associated with the presence of autoantibodies to aquaporin-4 (AQP4) as well as the mechanisms of astrocyte dysfunction and demyelination. Methods: An comprehensive search of the literature in the field was carried out using the database of The National Center for Biotechnology Information from . Systematic searches were performed until July 2022. Results: NMOSD is an inflammatory and demyelinating disease of the central nervous system mainly in the areas of the optic nerves and spinal cord, thus explaining mostly the clinical findings. Other areas affected in NMOSD are the brainstem, hypothalamus, and periventricular regions. Relapses in NMOSD are generally severe and patients only partially recover. NMOSD includes clinical conditions where autoantibodies to aquaporin-4 (AQP4-IgG) of astrocytes are detected as well as similar clinical conditions where such antibodies are not detected. AQP4 are channel-forming integral membrane proteins of which AQ4 isoforms are able to aggregate in supramolecular assemblies termed orthogonal arrays of particles (OAP) and are essential in the regulation of water homeostasis and the adequate modulation of neuronal activity and circuitry. AQP4 assembly in orthogonal arrays of particles is essential for AQP4-IgG pathogenicity since AQP4 autoantibodies bind to OAPs with higher affinity than for AQP4 tetramers. NMOSD has a complex background with prominent roles for genes encoding cytokines and cytokine receptors. AQP4 autoantibodies activate the complement-mediated inflammatory demyelination and the ensuing damage to AQP4 water channels, leading to water influx, necrosis and axonal loss. Conclusions: NMOSD as an astrocytopathy is a nosological entity different from multiple sclerosis with its own serological marker: immunoglobulin G-type autoantibodies against the AQP4 protein which elicits a complement-dependent cytotoxicity and neuroinflammation. Some patients with typical manifestations of NMSOD are AQP4 seronegative and myelin oligodendrocyte glycoprotein positive. Thus, the detection of autoantibodies against AQP4 or other autoantibodies is crucial for the correct treatment of the disease and immunosuppressant therapy is the first choice.

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Glutamate is one of the most abundant amino acids in the blood. Besides its role as a neurotransmitter in the brain, it is a key substrate in several metabolic pathways and a primary messenger that acts through its receptors outside the central nervous system (CNS). The two main types of glutamate receptors, ionotropic and metabotropic, are well characterized in CNS and have been recently analyzed for their roles in non-neural organs. Glutamate receptor expression may be particularly important for tumor growth in organs with high concentrations of glutamate and might also influence the propensity of such tumors to set metastases in glutamate-rich organs, such as the liver. The study of glutamate transporters has also acquired relevance in the physiology and pathologies outside the CNS, especially in the field of cancer research. In this review, we address the recent findings about the expression of glutamatergic system components, such as receptors and transporters, their role in the physiology and pathology of cancer in non-neural organs, and their possible use as biomarkers and therapeutic targets.

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The excitatory amino acid transporter EAAT3 plays an important role in the neuronal uptake of glutamate regulating the activation of glutamate receptors. Polymorphisms in the gene-encoding EAAT3 have been associated with obsessive-compulsive disorder (OCD), although the mechanisms underlying this relationship are still unknown. We recently reported that mice with increased EAAT3 expression in forebrain neurons (EAAT3 g lo /CMKII) display behavioral and synaptic features relevant to OCD, including increased grooming, higher anxiety-like behavior and altered cortico-striatal synaptic function. The dopamine neurotransmitter system is implicated in ritualistic behaviors. Indeed, dopaminergic neurons express EAAT3, and mice lacking EAAT3 exhibit decreased dopamine release and decreased expression of the dopamine D1 receptor. Moreover, EAAT3 plays a role on the effect of the psychostimulant amphetamine. As such, we sought to determine if the OCD-like behavior in EAAT3 g lo /CMKII mice is accompanied by altered nigro-striatal dopaminergic transmission. The aim of this study was to analyze dopamine transmission both in basal conditions and after an acute challenge of amphetamine, using behavioral, neurochemical, molecular, and cellular approaches. We found that in basal conditions, EAAT3 g lo /CMKII mice performed more grooming events and that they remained in phase 1 of the grooming chain syntax compared with control littermates. Administration of amphetamine increased the number of grooming events in control mice, while EAAT3 g lo /CMKII mice remain unaffected. Interestingly, the grooming syntax of amphetamine-control mice resembled that of EAAT3 g lo /CMKII mice in basal conditions. Using in vivo microdialysis, we found decreased basal dopamine levels in EAAT3 g lo /CMKII compared with control mice. Unexpectedly, we found that after acute amphetamine, EAAT3 g lo /CMKII mice had a higher release of dopamine compared with that of control mice, suggesting that EAAT3 overexpression leads to increased dopamine releasability. To determine postsynaptic effect of EAAT3 overexpression over dopamine transmission, we performed Western blot analysis of dopaminergic proteins and found that EAAT3 g lo /CMKII mice have higher expression of D2 receptors, suggesting a higher inhibition of the indirect striatal pathway. Together, the data indicate that EAAT3 overexpression impacts on dopamine transmission, making dopamine neurons more sensitive to the effect of amphetamine and leading to a disbalance between the direct and indirect striatal pathways that favors the performance of repetitive behaviors.

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Glutamate-mediated excitatory synaptic signalling is primarily controlled by excitatory amino acid transporters (EAATs), such as EAAT1 and EAAT2, which are located mostly on astrocytes and, together, uptake more than 95 % of extracellular glutamate. Alterations in the functional expression levels of EAATs can lead to excessive extracellular glutamate accumulation, potentially triggering excitotoxicity and seizures, among other neurological disorders. Excitotoxicity induced in early developmental stages can lead to lasting changes in several neurotransmission systems, including the glutamatergic system, which could make the brain more susceptible to a second insult. In this study, the expression levels of EAAT1 (GLAST) and EAAT2 (GLT-1) proteins were assessed in the cerebral motor cortex (CMC), striatum, hippocampus and entorhinal cortex (EC) of male adult rats following the neonatal excitotoxic process triggered by monosodium glutamate (MSG)-treatment (4 g/kg of body weight at postnatal days 1,3,5 and 7, subcutaneously). Western blot analysis showed that neonatal MSG-treatment decreased EAAT1 expression levels in the CMC, striatum and hippocampus, while EAAT2 levels were increased in the striatum and EC and decreased in the CMC. Immunofluorescence staining confirmed the changes in EAAT1 and EAAT2 expression induced by neonatal MSG-treatment, which were accompanied by an increase in the glial fibrillary acidic protein (GFAP) immunofluorescence signalthat was particularly significant in the hippocampus. Our results show that a neonatal excitotoxic processes can induce lasting changes in the expression levels of EAAT1 and EAAT2 proteins and suggest that although astrogliosis occurs, glutamate uptake could be deficient, particularly in the CMC and hippocampus.

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Glutamate is the main excitatory amino acid acting at the level of pre and postsynaptic neurons, as well as in glial cells. It is involved in the coordinated modulation of energy metabolism, glutamine synthesis, and ammonia detoxification. The relationship between the functional status of liver and brain has been known for many years. The most widely recognized aspect of this relation is the brain dysfunction caused by acute liver injury that manifests a wide spectrum of neurologic and psychiatric abnormalities. Inflammation, circulating neurotoxins, and impaired neurotransmission have been reported in this pathophysiology. In the present contribution, we report the effect of a hepatotoxic compound like CCl4 on the expression of key proteins involved in glutamate uptake and metabolism as glutamate transporters and glutamine synthetase in mice liver, brain, and cerebellum. Our findings highlight a differential expression pattern of glutamate transporters in cerebellum. A significant Purkinje cells loss, in parallel to an up-regulation of glutamine synthetase, and astrogliosis in the brain have also been noticed. In the intoxicated liver, glutamate transporter 1 expression is up-regulated, in contrast to glutamine synthetase which is reduced in a time-dependent manner. Taken together our results demonstrate that the exposure to an acute CCl4 insult, leads to the disruption of glutamate transporters expression in the liver-brain axis and therefore a severe alteration in glutamate-mediated neurotransmission might be present in the central nervous system.

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Obsessive compulsive disorder (OCD) is a heterogeneous psychiatric disorder affecting 1%-3% of the population worldwide. About half of OCD afflicted individuals do not respond to currently available pharmacotherapy, which is mainly based on serotonin reuptake inhibition. Therefore, there is a critical need to search novel and improved therapeutic targets to treat this devastating disorder. In recent years, accumulating evidence has supported the glutamatergic hypothesis of OCD, and particularly pointing a potential role for the neuronal glutamate transporter EAAT3. This mini-review summarizes recent findings regarding the neurobiological basis of OCD, with an emphasis on the glutamatergic neurotransmission and EAAT3 as a key player in OCD etiology.

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Our study aimed to analyze the effect of ouabain administration on lipopolysaccharide (LPS)-induced changes in oxidative parameters, membrane lipid composition, and the activities of some important enzymes of the nervous system. The content of phospholipids, cholesterol, and gangliosides were analyzed in Wistar rats after intraperitoneal injection of ouabain (1.8 µg/kg), LPS (200 µg/kg), or saline. Oxidative parameters were also evaluated, including the activities of superoxide dismutase, catalase and glutathione peroxidase, the levels of glutathione and lipid peroxidation, as well as Na,K-ATPase activity and the level of glutamate transporter EAAT4. Administration of LPS resulted in increased oxidative stress, as evidenced by an increase in lipid peroxidation levels, glutathione peroxidase activity, decreased catalase activity and reduced glutathione levels. All changes recorded were attenuated by pretreatment with ouabain. Administration of ouabain plus LPS enhanced the total ganglioside content and EAAT4 levels, but failed to alter the Na,K-ATPase activity. Our data suggest a neuroprotective effect of ouabain against LPS-induced oxidative stress by promoting membrane lipid remodeling and increasing the expression of glutamate transporter EAAT4. Our results emphasize that the observed oxidative stress is not correlated with Na,K-ATPase, but with a possible ouabain-mediated effect on cellular signaling. The relevance of our results extends beyond LPS-induced changes in oxidative parameters, as nanomolar doses of ouabain might prove useful in neurodegenerative models. Further study of other cardenolides and related molecules, as well as the development of new molecules derived from ouabain, could also prove useful in the fight against the oxidative and/or general cell stress triggered by neuronal pathologies.

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BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. RESULTS: Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. CONCLUSIONS: Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

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BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. RESULTS: Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. CONCLUSIONS: Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

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Dentro de los trastornos del estado de ánimo, los trastornos depresivos son padecimientos generalmente recurrentes que tienen, según las estadísticas, una prevalencia anual de un 3 % a un 6 % en la población. Desde la década de los 60' la hipótesis aminérgica de Schildkraut y posteriores, establecieron que las depresiones estaban vinculadas a alteraciones en la neurotransmisión catecolaminérgica y serotoninérgica. Los fármacos antidepresivos apuntaron a esas disfunciones pero las dificultades terapéuticas, retraso en el inicio de la acción y limitaciones en la eficacia, llevaron a la búsqueda de otras posibilidades, que surgieron de las investigaciones sobre la neurotransmisión glutamatérgica. En modelos animales se descubrió en los comienzos de los 90' la acción antidepresiva de los fármacos que antagonizaban la neurotransmisión de los receptores N-metil-D-aspartato (NMDA). El objetivo de este trabajo se orienta a establecer los fundamentos de la teoría glutamatérgica de las depresiones y a describir los fármacos que potencialmente podrían utilizarse en la clínica...

Depressive disorders are usually recurrent diseases that, according to statistics, afects from 3 % to 6 % of the population. Since the early '60s the Schildkraut aminergic hypothesis and subsequent, established that depressions were associated with alterations in cahtecolaminegic and serotonergic neurotransmission. Antidepressant drugs aimed at these dysfunctions but the therapeutic difficulties, delayed onset of action and efficacy limitations, led to the search of other possibilities that emerged from the research on glutamatergic neurotransmission. In animal models it was discovered in the early 90's the antidepressant action of drugs antagonized the NMDA receptor neurotransmission. The objective of this work is aimed at establishing the foundations of the glutamatergic theory of depressions and describe drugs that potentially could be used in the clinic...

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Glutamate, the major excitatory amino acid, activates a wide variety of signal transduction cascades. Ionotropic and metabotropic glutamate receptors are critically involved in long-term synaptic changes, although recent findings suggest that the electrogenic Na(+)-dependent glutamate transporters, responsible for its removal from the synaptic cleft participate in the signaling transactions triggered by this amino acid. Glutamate transporters are profusely expressed in glia therefore most of its uptake occurs in this cellular compartment. In the cerebellar cortex, Bergmann glial cells enwrap glutamatergic synapses and participate in the recycling of its neurotransmitter through the glutamate/glutamine shuttle. It has long been acknowledged that glutamatergic transmission in the cerebellar molecular layer results in cGMP accumulation within Bergmann glia cells. In this context, we decided to investigate a plausible role of the nitric oxide/cGMP-signaling pathway in the regulation of Bergmann glia glutamate transporters. To this end, the well-established model of primary cultures of chick cerebellar Bergmann glial cells was used. Confluent monolayers were exposed to the nitric oxide donor, sodium nitroprusside, or to the non-hydrolysable cGMP analog dbcGMP and the [(3)H] D-aspartate uptake activity measured. An increase in uptake activity, related to an augmentation in VMax, was detected with both treatments. The signaling cascade includes NO/cGMP/PKG and Ca(2+) influx through the Na(+)/Ca(2+) exchanger and might be related to the plasma membrane glutamate transporters turnover. Interestingly enough, an inhibitor of the cGMP dependent protein kinase was capable to abolish the sodium nitroprusside induced Ca(2+) influx. These results provide an insight into the physiological role of cGMP in the cerebellum.

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El glutamato, principal neurotransmisor excitatorio, está involucrado en mecanismos de plasticidad sináptica, memoria y muerte neuronal o glial, y el adecuado mantenimiento de sus niveles extracelulares es esencial para evitar la excitotoxicidad. En los últimos años se han producido muchos avances en el estudio de los transportadores de glutamato (VGLUTs y EAATs) encargados de su re-captura en las sinapsis. Haremos una revisión bibliográfica de sus propiedades, alteraciones producidas por su disfunción y posibles alternativas de neuroprotección. Así mismo revisaremos otro aspecto importante, la liberación de glutamato por los astrocitos bajo diversas situaciones patológicas, descubrimiento este de las últimas décadas de investigación sobre la glia (AU)

Glutamate, the major excitatory neurotransmitter, is involved in synaptic plasticity, memory and neuronal or glial death, and it is essential to proper maintenance of extracellular levels to prevent excitotoxicity. In recent years there have been many advances in the study of glutamate transporters (EAATs and VGLUTs) responsable for its re-capture at synapses. We will do a bibliographic review of their properties, changes caused by their dysfunction and possible alternatives for neuroprotection. We will also review antoher important aspect, the release of glutamate by astrocytes under different pathological conditions, discovered on the last decades by the research on glia (AU)

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El glutamato, principal neurotransmisor excitatorio, está involucrado en mecanismos de plasticidad sináptica, memoria y muerte neuronal o glial, y el adecuado mantenimiento de sus niveles extracelulares es esencial para evitar la excitotoxicidad. En los últimos años se han producido muchos avances en el estudio de los transportadores de glutamato (VGLUTs y EAATs) encargados de su re-captura en las sinapsis. Haremos una revisión bibliográfica de sus propiedades, alteraciones producidas por su disfunción y posibles alternativas de neuroprotección. Así mismo revisaremos otro aspecto importante, la liberación de glutamato por los astrocitos bajo diversas situaciones patológicas, descubrimiento este de las últimas décadas de investigación sobre la glia

Glutamate, the major excitatory neurotransmitter, is involved in synaptic plasticity, memory and neuronal or glial death, and it is essential to proper maintenance of extracellular levels to prevent excitotoxicity. In recent years there have been many advances in the study of glutamate transporters (EAATs and VGLUTs) responsable for its re-capture at synapses. We will do a bibliographic review of their properties, changes caused by their dysfunction and possible alternatives for neuroprotection. We will also review antoher important aspect, the release of glutamate by astrocytes under different pathological conditions, discovered on the last decades by the research on glia

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El glutamato, principal neurotransmisor excitatorio, está involucrado en mecanismos de plasticidad sináptica, memoria y muerte neuronal o glial, y el adecuado mantenimiento de sus niveles extracelulares es esencial para evitar la excitotoxicidad. En los últimos años se han producido muchos avances en el estudio de los transportadores de glutamato (VGLUTs y EAATs) encargados de su re-captura en las sinapsis. Haremos una revisión bibliográfica de sus propiedades, alteraciones producidas por su disfunción y posibles alternativas de neuroprotección. Así mismo revisaremos otro aspecto importante, la liberación de glutamato por los astrocitos bajo diversas situaciones patológicas, descubrimiento este de las últimas décadas de investigación sobre la glia (AU)

Glutamate, the major excitatory neurotransmitter, is involved in synaptic plasticity, memory and neuronal or glial death, and it is essential to proper maintenance of extracellular levels to prevent excitotoxicity. In recent years there have been many advances in the study of glutamate transporters (EAATs and VGLUTs) responsable for its re-capture at synapses. We will do a bibliographic review of their properties, changes caused by their dysfunction and possible alternatives for neuroprotection. We will also review antoher important aspect, the release of glutamate by astrocytes under different pathological conditions, discovered on the last decades by the research on glia (AU)

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