Gliotransmitters travel in time and space Araque, Alfonso; Carmignoto, Giorgio; Haydon, Philip G ...
Neuron (Cambridge, Mass.),
02/2014, Letnik:
81, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, ...we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.
Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory. The classical form of LTP relies on N-methyl-d-aspartate receptors (NMDARs), ...and it has been shown that astroglia can regulate their activation through Ca2+-dependent release of the NMDAR co-agonist d-serine. Release of d-serine from glia enables LTP in cultures and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus. However, increases in Ca2+ concentration in astroglia can also release other signalling molecules, most prominently glutamate, ATP and tumour necrosis factor- , whereas neurons themselves can synthesize and supply d-serine. Furthermore, loading an astrocyte with exogenous Ca2+ buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca2+ in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous d-serine or glycine, whereas depletion of d-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca2+-dependent release of d-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glial cells in (patho)physiology Parpura, Vladimir; Heneka, Michael T.; Montana, Vedrana ...
Journal of neurochemistry,
April 2012, Letnik:
121, Številka:
1
Journal Article
Recenzirano
Odprti dostop
J. Neurochem. (2012) 121, 4–27.
Neuroglial cells define brain homeostasis and mount defense against pathological insults. Astroglia regulate neurogenesis and development of brain circuits. In the ...adult brain, astrocytes enter into intimate dynamic relationship with neurons, especially at synaptic sites where they functionally form the tripartite synapse. At these sites, astrocytes regulate ion and neurotransmitter homeostasis, metabolically support neurons and monitor synaptic activity; one of the readouts of the latter manifests in astrocytic intracellular Ca2+ signals. This form of astrocytic excitability can lead to release of chemical transmitters via Ca2+‐dependent exocytosis. Once in the extracellular space, gliotransmitters can modulate synaptic plasticity and cause changes in behavior. Besides these physiological tasks, astrocytes are fundamental for progression and outcome of neurological diseases. In Alzheimer’s disease, for example, astrocytes may contribute to the etiology of this disorder. Highly lethal glial‐derived tumors use signaling trickery to coerce normal brain cells to assist tumor invasiveness. This review not only sheds new light on the brain operation in health and disease, but also points to many unknowns.
N-methyl d-aspartate receptors (NMDARs) exist in different forms owing to multiple combinations of subunits that can assemble into a functional receptor. In addition, they are located not only at ...synapses but also at extrasynaptic sites. There has been intense speculation over the past decade about whether specific NMDAR subtypes and/or locations are responsible for inducing synaptic plasticity and excitotoxicity. Here, we review the latest findings on the organization, subunit composition and endogenous control of NMDARs at extrasynaptic sites and consider their putative functions. Because astrocytes are capable of controlling NMDARs through the release of gliotransmitters, we also discuss the role of the glial environment in regulating the activity of these receptors.
N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological ...processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology.
Display omitted
► Synaptic and extrasynaptic NMDARs are gated by d-serine and glycine, respectively ► d-serine and glycine differentially impact NMDAR membrane diffusion ► Synaptic NMDARs mediate LTP and excitotoxicity ► Both synaptic and extrasynaptic receptors are required for LTD induction
NMDA receptors present in the synapse are gated by different amino acids than those located outside of the synapse in neuronal membranes. This differential gating enabled dissection of distinct functional roles for each pool of receptors and led to the surprising finding that glutamate toxicity and long-term potentiation are mediated solely by synaptic NMDARs
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.
Neurocenter Magendie, Institut National de la Santé et de la Recherche Médicale U. 862 and University Victor Segalen-Bordeaux 2, Bordeaux, France
Observations from different brain areas have ...established that the adult nervous system can undergo significant experience-related structural changes throughout life. Less familiar is the notion that morphological plasticity affects not only neurons but glial cells as well. Yet there is abundant evidence showing that astrocytes, the most numerous cells in the mammalian brain, are highly mobile. Under physiological conditions as different as reproduction, sensory stimulation, and learning, they display a remarkable structural plasticity, particularly conspicuous at the level of their lamellate distal processes that normally ensheath all portions of neurons. Distal astrocytic processes can undergo morphological changes in a matter of minutes, a remodeling that modifies the geometry and diffusion properties of the extracellular space and relationships with adjacent neuronal elements, especially synapses. Astrocytes respond to neuronal activity via ion channels, neurotransmitter receptors, and transporters on their processes; they transmit information via release of neuroactive substances. Where astrocytic processes are mobile then, astrocytic-neuronal interactions become highly dynamic, a plasticity that has important functional consequences since it modifies extracellular ionic homeostasis, neurotransmission, gliotransmission, and ultimately neuronal function at the cellular and system levels. Although a complete picture of intervening cellular mechanisms is lacking, some have been identified, notably certain permissive molecular factors common to systems capable of remodeling (cell surface and extracellular matrix adhesion molecules, cytoskeletal proteins) and molecules that appear specific to each system (neuropeptides, neurotransmitters, steroids, growth factors) that trigger or reverse the morphological changes.
Control of the glutamate time course in the synapse is crucial for excitatory transmission. This process is mainly ensured by astrocytic transporters, high expression of which is essential to ...compensate for their slow transport cycle. Although molecular mechanisms regulating transporter intracellular trafficking have been identified, the relationship between surface transporter dynamics and synaptic function remains unexplored. We found that GLT-1 transporters were highly mobile on rat astrocytes. Surface diffusion of GLT-1 was sensitive to neuronal and glial activities and was strongly reduced in the vicinity of glutamatergic synapses, favoring transporter retention. Notably, glutamate uncaging at synaptic sites increased GLT-1 diffusion, displacing transporters away from this compartment. Functionally, impairing GLT-1 membrane diffusion through cross-linking in vitro and in vivo slowed the kinetics of excitatory postsynaptic currents, indicative of a prolonged time course of synaptic glutamate. These data provide, to the best of our knowledge, the first evidence for a physiological role of GLT-1 surface diffusion in shaping synaptic transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract
Astrocytic Ca
2+
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 Ca
2+
imaging showed that nodes were biochemical compartments and Ca
2+
microdomains. Mapping astrocytic Ca
2+
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.
PDF
