Astroglial processes show spontaneous motility at active synaptic terminals <i>in situ</i>

Hirrlinger, Johannes; Hülsmann, Swen; Kirchhoff, Frank

doi:10.1111/j.1460-9568.2004.03689.x

Cited by 253 publications

(209 citation statements)

References 29 publications

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“…This finding is in agreement with previous results showing that astroglial process endings are dynamic and change their morphology rapidly (within minutes) (Hirrlinger et al, 2004). Crucially, one of the principle tasks of the astrocytes is the synthesis and release of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) (Althaus and Richter-Landsberg, 2000) and the antidepressant effect of traditional antidepressant drugs and ketamine have been shown to be dependent on the hippocampal level of BDNF (Duman and Monteggia, 2006;Monteggia et al, 2013).…”

Section: Discussionsupporting

confidence: 82%

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

Ardalan

Rafati

Nyengaard

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEAstroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes' morphology in a genetic animal model of depression. EXPERIMENTAL APPROACHS-Ketamine (15 mg·kg À1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test. KEY RESULTSFSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment. CONCLUSIONS AND IMPLICATIONSOur results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour. AbbreviationsBDNF, brain-derived neurotrophic factor; CA1.SR, CA1 stratum radiatum; EAAT, excitatory amino acid transporter; FRL, Flinders resistant line; FSL, Flinders sensitive line; GCL, granular cell layer of dentate gyrus; GFAP, glial fibrillary acid protein; MDG, molecular layer of dentate gyrus

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Section: Discussionsupporting

confidence: 82%

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

Ardalan

Rafati

Nyengaard

et al. 2017

British J Pharmacology

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“…2A and Fig. S4), as expected from previous studies (5,6). The receptors mediating this process were investigated by the use of glutamate analogues (Fig.…”

Section: Resultsmentioning

confidence: 96%

Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors

Lavialle

Aumann

Anlauf

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

233

264

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The peripheral astrocyte process (PAP) preferentially associates with the synapse. The PAP, which is not found around every synapse, extends to or withdraws from it in an activity-dependent manner. Although the pre-and postsynaptic elements have been described in great molecular detail, relatively little is known about the PAP because of its difficult access for electrophysiology or light microscopy, as they are smaller than microscopic resolution. We investigated possible stimuli and mechanisms of PAP plasticity. Immunocytochemistry on rat brain sections demonstrates that the actin-binding protein ezrin and the metabotropic glutamate receptors (mGluRs) 3 and 5 are compartmentalized to the PAP but not to the GFAP-containing stem process. Further experiments applying ezrin siRNA or dominant-negative ezrin in primary astrocytes indicate that filopodia formation and motility require ezrin in the membrane/cytoskeleton bound (i.e., T567-phosphorylated) form. Glial processes around synapses in situ consistently display this ezrin form. Possible motility stimuli of perisynaptic glial processes were studied in culture, based on their similarity with filopodia. Glutamate and glutamate analogues reveal that rapid (5 min), glutamate-induced filopodia motility is mediated by mGluRs 3 and 5. Ultrastructurally, these mGluR subtypes were also localized in astrocytes in the rat hippocampus, preferentially in their fine PAPs. In vivo, changes in glutamatergic circadian activity in the hamster suprachiasmatic nucleus are accompanied by changes of ezrin immunoreactivity in the suprachiasmatic nucleus, in line with transmitter-induced perisynaptic glial motility. The data suggest that (i) ezrin is required for the structural plasticity of PAPs and (ii) mGluRs can stimulate PAP plasticity.A strocytes act as a third partner in synaptic signal processing by responding to neurotransmitters and by releasing "gliotransmitters" (1, 2). Structurally, the astrocyte functions mainly through its peripheral processes, which constitute approximately 80% of the cell's membrane (3). These peripheral astrocyte processes (PAPs) are frequently extremely fine (<50 nm) and display an extreme surface-to-volume ratio. They are rarely studied in live tissue, as they are not directly accessible to electrophysiology, cannot be isolated for biochemistry, and are smaller than microscopic resolution. However, they also wrap synapses, but most studies on glia-synaptic interaction can only indiscriminately refer to them as the astrocyte. At the ultrastructural level, the PAPs, although abundant in the neuropil, specifically prefer contacting synapses and dendrites versus axons (4). The synaptic wrapping is highly dynamic (5-9) and also activity-dependent even in the context of physiological functions, such as motor learning, daily fluctuations of the circadian clock, lactation, parturition, or dehydration (10-15). Here, we asked two questions about the structural basis of glia-synaptic interaction: What is the stimulus for PAP plasticity, and what are the intra...

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“…Astrocytic oxidative capability resides in the soma and larger cell processes (Figure 1) that contain the mitochondria (Wolff and Chao, 2004). Threadlike filopodia (B3 mm long by B0.2 mm wide) and the equally thin, sheet-like lamellipodia account for B40% of the cell volume, and are highly mobile (Hirrlinger et al, 2004). These peripheral astrocyte processes ( Figure 1A) constitute a specific compartment (Derouiche and Frotscher, 2001) that cannot accommodate mitochondria, which are approximately twice as wide.…”

Section: Discussionmentioning

confidence: 99%

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

Hertz

Peng

Dienel

2007

J Cereb Blood Flow Metab

526

573

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Astrocytic energy demand is stimulated by K + and glutamate uptake, signaling processes, responses to neurotransmitters, Ca 2 + fluxes, and filopodial motility. Astrocytes derive energy from glycolytic and oxidative pathways, but respiration, with its high-energy yield, provides most adenosine 5 0 triphosphate (ATP). The proportion of cortical oxidative metabolism attributed to astrocytes (B30%) in in vivo nuclear magnetic resonance (NMR) spectroscopic and autoradiographic studies corresponds to their volume fraction, indicating similar oxidation rates in astrocytes and neurons. Astrocyte-selective expression of pyruvate carboxylase (PC) enables synthesis of glutamate from glucose, accounting for two-thirds of astrocytic glucose degradation via combined pyruvate carboxylation and dehydrogenation. Together, glutamate synthesis and oxidation, including neurotransmitter turnover, generate almost as much energy as direct glucose oxidation. Glycolysis and glycogenolysis are essential for astrocytic responses to increasing energy demand because astrocytic filopodial and lamellipodial extensions, which account for 80% of their surface area, are too narrow to accommodate mitochondria; these processes depend on glycolysis, glycogenolysis, and probably diffusion of ATP and phosphocreatine formed via mitochondrial metabolism to satisfy their energy demands. High glycogen turnover in astrocytic processes may stimulate glucose demand and lactate production because less ATP is generated when glucose is metabolized via glycogen, thereby contributing to the decreased oxygen to glucose utilization ratio during brain activation. Generated lactate can spread from activated astrocytes via low-affinity monocarboxylate transporters and gap junctions, but its subsequent fate is unknown. Astrocytic metabolic compartmentation arises from their complex ultrastructure; astrocytes have high oxidative rates plus dependence on glycolysis and glycogenolysis, and their energetics is underestimated if based solely on glutamate cycling. Keywords: acetate; glucose metabolism; glutamate; neurotransmitters; potassium; pyruvate carboxylation Introduction Astrocytes are More Than HousekeepersRecent studies in many different fields have shown much more active roles of astrocytes in brain function than previously portrayed by their traditionally ascribed 'bystander or housekeeping' functions. Emerging roles of astrocytes include their interactions with the vasculature, neurons, and other astrocytes via signaling, biosynthetic, and transport processes to regulate blood flow, modulate impulse transmission, and synthesize and degrade glucose-derived neurotransmitters, for example, glutamate and g-aminobutyric acid (GABA) (Takano et al, 2006;Hertz and Zielke, 2004;Volterra and Meldolesi, 2005). All of these processes are energyrequiring or dependent on energy-related metabolic pathways, thereby directly linking astrocyte functions, energetics, and metabolite fluxes.The narrow astrocytic surface extensions (lamellae and filopodia, also called peripheral ast...

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Astroglial processes show spontaneous motility at active synaptic terminals in situ

Cited by 253 publications

References 29 publications

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

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