RESUMEN
Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of D-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter D-serine, by its precursor L-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards L-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.
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Astrocitos , Cognición , Glucólisis , Ácido Láctico , Ratones Noqueados , Serina , Animales , Masculino , Astrocitos/metabolismo , Cognición/fisiología , Ratones , Ácido Láctico/metabolismo , Serina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Hipocampo/metabolismo , Sinapsis/metabolismo , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Recent work from Bonvento and colleagues indicated that synaptic and memory deficits in early Alzheimer's disease (AD) are related to a shortage in L-serine production in astrocytes. Here, the authors, responding to correspondence from Chen and colleagues, discuss how this deficiency does not necessarily require a decrease in PHGDH expression and conclude that the primary event leading to lower serine production is more likely related to altered glycolytic flux in early AD than to PHGDH expression.
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Enfermedad de Alzheimer , Serina , Enfermedad de Alzheimer/metabolismo , Astrocitos/metabolismo , Glucólisis , Humanos , Fosfoglicerato-Deshidrogenasa/metabolismo , Serina/metabolismoRESUMEN
Astrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, D-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via Gi/o and Gq, to the intracellular Ca2+ release channel IP3-receptor (IP3R). Indeed, manipulating astrocytic IP3R-Ca2+ signaling is highly consequential at the network and behavioral level: Depleting IP3R subtype 2 (IP3R2) results in reduced GPCR-Ca2+ signaling and impaired synaptic plasticity; enhancing IP3R-Ca2+ signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP3R-Ca2+ signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP3R2 has been used to represent all astrocytic IP3Rs, including IP3R1 and IP3R3. Indeed, IP3R1 and IP3R3 are unique Ca2+ channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP3R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca2+ dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte-neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP3R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca2+ dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP3R isoform.
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Synaptic plasticity is an extensively studied cellular correlate of learning and memory in which NMDARs play a starring role. One of the most interesting features of NMDARs is their ability to act as a co-incident detector. It is unique amongst neurotransmitter receptors in this respect. Co-incident detection is possible because the opening of NMDARs requires membrane depolarisation and the binding of glutamate. Opening of NMDARs also requires a co-agonist. Although the dynamic regulation of glutamate and membrane depolarization have been well studied in coincident detection, the role of the co-agonist site is unexplored. It turns out that non-neuronal glial cells, astrocytes, regulate co-agonist availability, giving them the ability to influence synaptic plasticity. The unique morphology and spatial arrangement of astrocytes at the synaptic level affords them the capacity to sample and integrate information originating from unrelated synapses, regardless of any pre-synaptic and post-synaptic commonality. As astrocytes are classically considered slow responders, their influence at the synapse is widely recognized as modulatory. The aim herein is to reconsider the potential of astrocytes to participate directly in ongoing synaptic NMDAR activity and co-incident detection.
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Astrocitos/metabolismo , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Ácido Glutámico/metabolismo , Humanos , Plasticidad Neuronal/fisiología , Sinapsis/metabolismoRESUMEN
Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
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Envejecimiento/patología , Astrocitos/patología , Encéfalo/patología , Médula Espinal/patología , Animales , Encefalopatías/patología , Lesiones Encefálicas/patología , Humanos , Traumatismos de la Médula Espinal/patologíaRESUMEN
Extrasynaptic actions of glutamate are limited by high-affinity transporters expressed by perisynaptic astroglial processes (PAPs): this helps maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodeling, but how this affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here, we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and 3D molecular localization reveal that LTP induction thus prompts spatial retreat of astroglial glutamate transporters, boosting glutamate spillover and NMDA-receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We have therefore uncovered a mechanism by which a memory trace at one synapse could alter signal handling by multiple neighboring connections.
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Astrocitos/metabolismo , Ácido Glutámico/metabolismo , Potenciación a Largo Plazo/fisiología , Sinapsis/metabolismo , Animales , Astrocitos/ultraestructura , Femenino , Imagenología Tridimensional/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Sinapsis/ultraestructuraRESUMEN
The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
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Envejecimiento/fisiología , Encéfalo/fisiología , Metabolismo Energético/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Animales , Glucólisis/fisiología , Humanos , Fosforilación OxidativaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Astrocytic Ca2+ signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. However, the anatomical basis of such specific signaling remains unclear, owing to difficulties in resolving the spongiform domain of astrocytes where most tripartite synapses are located. Using 3D-STED microscopy in living organotypic brain slices, we imaged the spongiform domain of astrocytes and observed a reticular meshwork of nodes and shafts that often formed loop-like structures. These anatomical features were also observed in acute hippocampal slices and in barrel cortex in vivo. The majority of dendritic spines were contacted by nodes and their sizes were correlated. FRAP experiments and Ca2+ imaging showed that nodes were biochemical compartments and Ca2+ microdomains. Mapping astrocytic Ca2+ signals onto STED images of nodes and dendritic spines showed they were associated with individual synapses. Here, we report on the nanoscale organization of astrocytes, identifying nodes as a functional astrocytic component of tripartite synapses that may enable synapse-specific communication between neurons and astrocytes.
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Astrocitos/citología , Astrocitos/metabolismo , Señalización del Calcio/fisiología , Sinapsis/metabolismo , Animales , Encéfalo , Calcio/metabolismo , Hipocampo , Imagenología Tridimensional , Masculino , Ratones , Microscopía , Neuronas/metabolismoRESUMEN
Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic l-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. l-serine is the precursor of d-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the l-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic l-serine. Supplementation with l-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral l-serine as a ready-to-use therapy for AD.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Disfunción Cognitiva/metabolismo , Glucólisis , Serina/biosíntesis , Administración Oral , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Animales , Astrocitos/efectos de los fármacos , Sitios de Unión , Encéfalo/patología , Encéfalo/fisiopatología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Metabolismo Energético/efectos de los fármacos , Femenino , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Plasticidad Neuronal/efectos de los fármacos , Fosfoglicerato-Deshidrogenasa/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/administración & dosificación , Serina/farmacología , Serina/uso terapéutico , Memoria Espacial/efectos de los fármacosRESUMEN
Astrocytes constantly adapt their ramified morphology in order to support brain cell assemblies. Such plasticity is partly mediated by ion and water fluxes, which rely on the water channel aquaporin-4 (AQP4). The mechanism by which this channel locally contributes to process dynamics has remained elusive. Using a combination of single-molecule and calcium imaging approaches, we here investigated in hippocampal astrocytes the dynamic distribution of the AQP4 isoforms M1 and M23. Surface AQP4-M1 formed small aggregates that contrast with the large AQP4-M23 clusters that are enriched near glutamatergic synapses. Strikingly, stabilizing surface AQP4-M23 tuned the motility of astrocyte processes and favors glutamate synapse activity. Furthermore, human autoantibodies directed against AQP4 from neuromyelitis optica (NMO) patients impaired AQP4-M23 dynamic distribution and, consequently, astrocyte process and synaptic activity. Collectively, it emerges that the membrane dynamics of AQP4 isoform regulate brain cell assemblies in health and autoimmune brain disease targeting AQP4.
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Acuaporina 4/inmunología , Astrocitos/inmunología , Hipocampo/inmunología , Neuromielitis Óptica/inmunología , Sinapsis/inmunología , Animales , Astrocitos/patología , Autoanticuerpos/inmunología , Calcio/inmunología , Hipocampo/patología , Humanos , Neuromielitis Óptica/patología , Transporte de Proteínas/inmunología , Ratas , Ratas Sprague-Dawley , Sinapsis/patologíaRESUMEN
BACKGROUND: Spinal reactive astrocytes and microglia are known to participate to the initiation and maintenance of neuropathic pain. However, whether reactive astrocytes and microglia in thalamic nuclei that process sensory-discriminative aspects of pain play a role in pain behavior remains poorly investigated. Therefore, the present study evaluated whether the presence of reactive glia (hypertrophy, increased number and upregulation of glial markers) in the ventral posterolateral thalamic nucleus (VPL) correlates with pain symptoms, 14 and 28 days after unilateral L5/L6 spinal nerve ligation (SNL) in rats. METHODS: Mechanical allodynia and hyperalgesia (von Frey filament stimulation) as well as ambulatory pain (dynamic weight bearing apparatus) were assessed. Levels of nine glial transcripts were determined by quantitative real-time PCR on laser microdissected thalamic nuclei, and levels of proteins were assessed by Western blot. We also studied by immunohistofluorescence the expression of glial markers that label processes (GFAP for astrocytes and iba-1 for microglia) and cell body (S100ß for astrocytes and iba-1 for microglia) and quantified the immunostained surface and the number of astrocytes and microglia (conventional counts and optical dissector method of stereological counting). RESULTS: Differential, time-dependent responses were observed concerning microglia and astrocytes. Specifically, at day 14, iba-1 immunostained area and number of iba-1 immunopositive cells were decreased in the VPL of SNL as compared to naïve rats. By contrast, at day 28, GFAP-immunostained area was increased in the VPL of SNL as compared to naïve rats while number of GFAP/S100ß immunopositive cells remained unchanged. Using quantitative real-time PCR of laser microdissected VPL, we found a sequential increase in mRNA expression of cathepsin S (day 14), fractalkine (day 28), and fractalkine receptor (day 14), three well-known markers of microglial reactivity. Using Western blot, we confirmed an increase in protein expression of fractalkine receptor at day 14. CONCLUSIONS: Our results demonstrate a sequential alteration of microglia and astrocytes in the thalamus of animals with lesioned peripheral nerves. Furthermore, our data report unprecedented concomitant molecular signs of microglial activation and morphological signs of microglial decline in the thalamus of these animals.
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Astrocitos/metabolismo , Regulación de la Expresión Génica/fisiología , Microglía/metabolismo , Traumatismos de los Nervios Periféricos/patología , Nervios Espinales/lesiones , Tálamo/patología , Animales , Astrocitos/patología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Ligadura , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Microglía/patología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/etiología , Dimensión del Dolor , Umbral del Dolor/fisiología , Traumatismos de los Nervios Periféricos/complicaciones , Ratas , Ratas Sprague-Dawley , Estadísticas no Paramétricas , Tálamo/metabolismoRESUMEN
Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer's disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer's disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer's disease.
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Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Astrocitos/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Apolipoproteínas E/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/citología , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Mutación/genética , Presenilina-1/genética , Presenilina-1/metabolismo , Factor de Transcripción STAT1/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB1 receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB1 receptors from astroglial cells (GFAP-CB1-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB1 receptors increased intracellular astroglial Ca2+ levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB1-KO displayed lower occupancy of the co-agonist binding site of synaptic hippocampal NMDARs. Finally, elevation of D-serine levels fully rescued LTP and memory impairments of GFAP-CB1-KO mice. These data reveal a novel mechanism of in vivo astroglial control of memory and synaptic plasticity via the D-serine-dependent control of NMDARs.
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Astrocitos/metabolismo , Neuronas/metabolismo , Receptor Cannabinoide CB1/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Reconocimiento en Psicología/fisiología , Serina/metabolismo , Sinapsis/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Región CA3 Hipocampal/metabolismo , Hipocampo , Técnicas In Vitro , Potenciación a Largo Plazo , Memoria , Ratones , Ratones Noqueados , Plasticidad Neuronal , Receptor Cannabinoide CB1/metabolismoRESUMEN
The surface dynamics of neurotransmitter receptors and transporters, as well as ion channels, has been well-documented in neurons, revealing complex molecular behaviour and key physiological functions. However, our understanding of the membrane trafficking and dynamics of the signalling molecules located at the plasma membrane of glial cells is still in its infancy. Yet, recent breakthroughs in the field of glial cells have been obtained using combination of superresolution microscopy, single molecule imaging, and electrophysiological recordings. Here, we review our current knowledge on the surface dynamics of neurotransmitter receptors, transporters and ion channels, in glial cells. It has emerged that the brain cell network activity, synaptic activity, and calcium signalling, regulate the surface distribution and dynamics of these molecules. Remarkably, the dynamics of a given neurotransmitter receptor/transporter at the plasma membrane of a glial cell or neuron is unique, revealing the existence of cell-type specific regulatory pathways. Thus, investigating the dynamics of signalling proteins at the surface of glial cells will likely shed new light on our understanding of glial cell physiology and pathology.
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Encéfalo/metabolismo , Señalización del Calcio , Canales Iónicos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Neuroglía/metabolismo , Receptores de Neurotransmisores/metabolismo , Animales , Astrocitos/citología , Astrocitos/metabolismo , Encéfalo/citología , Membrana Celular/metabolismo , Regulación de la Expresión Génica , Ácido Glutámico/metabolismo , Humanos , Canales Iónicos/genética , Proteínas de Transporte de Membrana/genética , Neuroglía/citología , Neuronas/citología , Neuronas/metabolismo , Especificidad de Órganos , Transporte de Proteínas , Receptores de Neurotransmisores/genética , Imagen Individual de Molécula , Sinapsis/fisiologíaRESUMEN
Planar cell polarity (PCP) signaling is well known to play a critical role during prenatal brain development; whether it plays specific roles at postnatal stages remains rather unknown. Here, we investigated the role of a key PCP-associated gene scrib in CA1 hippocampal structure and function at postnatal stages. We found that Scrib is required for learning and memory consolidation in the Morris water maze as well as synaptic maturation and NMDAR-dependent bidirectional plasticity. Furthermore, we unveiled a direct molecular interaction between Scrib and PP1/PP2A phosphatases whose levels were decreased in postsynaptic density of conditional knock-out mice. Remarkably, exposure to enriched environment (EE) preserved memory formation in CaMK-Scrib-/- mice by recovering synaptic plasticity and maturation. Thus, Scrib is required for synaptic function involved in memory formation and EE has beneficiary therapeutic effects. Our results demonstrate a distinct new role for a PCP-associated protein, beyond embryonic development, in cognitive functions during adulthood.
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Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/terapia , Ambiente , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Plasticidad Neuronal/fisiología , Animales , Células COS , Chlorocebus aethiops , Disfunción Cognitiva/patología , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Hipocampo/ultraestructura , Vivienda para Animales , Péptidos y Proteínas de Señalización Intracelular/genética , Discapacidades para el Aprendizaje/patología , Discapacidades para el Aprendizaje/fisiopatología , Discapacidades para el Aprendizaje/terapia , Masculino , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/terapia , Ratones Noqueados , Modelos Moleculares , Densidad Postsináptica/metabolismo , Densidad Postsináptica/ultraestructura , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/ultraestructuraRESUMEN
Astrocytes, the major glial cell type in the central nervous system (CNS), are critical for brain function and have been implicated in various disorders of the central nervous system. These cells are involved in a wide range of cerebral processes including brain metabolism, control of central blood flow, ionic homeostasis, fine-tuning synaptic transmission, and neurotransmitter clearance. Such varied roles can be efficiently carried out due to the intimate interactions astrocytes maintain with neurons, the vasculature, as well as with other glial cells. Arguably, one of the most important functions of astrocytes in the brain is their control of neurotransmitter clearance. This is particularly true for glutamate whose timecourse in the synaptic cleft needs to be controlled tightly under physiological conditions to maintain point-to-point excitatory transmission, thereby limiting spillover and activation of more receptors. Most importantly, accumulation of glutamate in the extracellular space can trigger excessive activation of glutamatergic receptors and lead to excitotoxicity, a trademark of many neurodegenerative diseases. It is thus of utmost importance for both physiological and pathophysiological reasons to understand the processes that control glutamate time course within the synaptic cleft and regulate its concentrations in the extracellular space. © 2017 Wiley Periodicals, Inc.
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Sistema de Transporte de Aminoácidos X-AG/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Homeostasis/fisiología , Neurotransmisores/fisiología , Transmisión Sináptica/fisiología , Animales , Astrocitos/patología , Encéfalo/patología , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
Fluoroacetate has been widely used to inhibit glia metabolism in vivo. It has yet to be shown what the effects of chronic intrathecal infusion of fluoroacetate on nociceptive behavioral testing are. The effects of chronic infusion of fluoroacetate (5 nmoles/h) for 2 weeks were examined in normal rats. Chronic intrathecal fluoroacetate did not alter mechanical threshold (von Frey filaments), responses to supra-threshold mechanical stimuli (von Frey filaments), responses to hot (hot plate) or cool (acetone test) stimuli and did not affect motor performance of the animals, which was tested with rotarod. This suggests that fluoroacetate at appropriate dose did not suppress neuronal activity in the spinal cord.
RESUMEN
Activation of N-methyl-d-aspartate (NMDA) receptors is critical for hypersensitivity in chronic neuropathic pain. Since astroglia can regulate NMDA receptor activation by releasing the NMDA receptor co-agonist d-serine, we investigated the role of NMDA receptor and d-serine in neuropathic chronic pain. Male Wistar rats underwent right L5-L6 spinal nerve ligation or sham surgery and were tested for mechanical allodynia and hyperalgesia after 14 days. Acute intrathecal administration of the NMDA receptor antagonist d-AP5 as well as chronic administration of the glia metabolism inhibitor fluoroacetate significantly reduced mechanical allodynia in neuropathic rats. The effect of fluoroacetate was reversed by acutely administered intrathecal d-serine. Degrading d-serine using acute intrathecal administration of d-aminoacid oxidase also reduced pain symptoms. Immunocytochemistry showed that about 70% of serine racemase, the synthesizing enzyme of d-serine, was expressed in astrocyte processes in the superficial laminae of L5 dorsal horn. Serine racemase expression was upregulated in astrocyte processes in neuropathic rats compared to sham rats. These results show that neuropathic pain depends upon glial d-serine that co-activates spinal NMDA receptors.