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

Article (PDF Available)inProceedings of the National Academy of Sciences 108(31):12915-9 · August 2011with29 Reads
DOI: 10.1073/pnas.1100957108 · Source: PubMed
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.


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Available from: Amin Derouiche
    • "In the electron microscopic analyses, we observed GFP-positive perisynaptic processes that were closely apposed to synapses (Figure 1G). In the past two decades, accumulating evidence has demonstrated that perisynaptic astrocytic processes (PAPs) are dynamic elements involved in reciprocal communication between astrocytes and neurons (Volterra and Meldolesi, 2005; Halassa et al., 2007; Allen and Barres, 2009; Gruber, 2009; Perea et al., 2009; Eroglu and Barres, 2010; Dityatev and Rusakov, 2011; Lavialle et al., 2011; Patrushev et al., 2013; Bernardinelli et al., 2014). This communication takes place at a ''tripartite synapse'' consisting of pre-and postsynaptic neurons and PAPs. "
    [Show abstract] [Hide abstract] ABSTRACT: Changes in astrocyte morphology are primarily attributed to the fine processes where intimate connections with neurons form the tripartite synapse and participate in neurotransmission. Recent evidence has shown that neurotransmission induces dynamic synaptic remodeling, suggesting that astrocytic fine processes may adapt their morphologies to the activity in their environment. To illustrate such a neuron-glia relationship in morphological detail, we employed a double transgenic Olig2 CreER/WT ; ROSA26-GAP43-EGFP mice, in which Olig2-lineage cells can be visualized and traced with membrane-targeted GFP. Although Olig2-lineage cells in the adult brain usually become mature oligodendrocytes or oligodendrocyte precursor cells with NG2-proteoglycan expression, we found a population of Olig2-lineage astrocytes with bushy morphology in several brain regions. The globus pallidus (GP) preferentially contains Olig2-lineage astrocytes. Since the GP exerts pivotal motor functions in the indirect pathway of the basal ganglionic circuit, we subjected the double transgenic mice to voluntary wheel running to activate the GP and examined morphological changes of Olig2-lineage astrocytes at both the light and electron microscopic levels. The double transgenic mice were divided into three groups: control group mice were kept in a cage with a locked running wheel for 3 weeks, Runner group were allowed free access to a running wheel for 3 weeks, and the Runner-Rest group took a sedentary 3-week rest after a 3-week running period. GFP immunofluorescence analysis and immunoelectron microscopy revealed that astrocytic fine processes elaborated complex arborization in the Runner mice, and reverted to simple morphology comparable to that of the Control group in the Runner-Rest group. Our results indicated that the fine processes of the Olig2-lineage astrocytes underwent plastic changes that correlated with overall running activities, suggesting that they actively participate in motor functions.
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    • "Of particular interest might be the differential regulation of the astroglial proteins ezrin (down), glutamine synthetase (up), and aquaporin-4 (down) specifically in the HIP. The actin cytoskeleton-associated protein ezrin is a key component of peripheral astrocytic processes (PAP) associated with synapses and critical for motility of these fine processes and thereby the structural plasticity of PAPs (Lavialle et al. 2011 ). In conjunction with the downregulation of aquaporin-4, which is generally positively correlated with astroglial volume and may regulate 'adaptive swelling' of PAPs (Nagelhus et al. 2004), and increased levels of glutamine synthetase, reciprocal alterations in synaptic activity might be directly reflected on the level of the tripartite synapse (Clarke and Barres 2013). "
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    • "Eriksson et al. (1995) reported that sodium-dependent uptake of 100 mol/L glutamate stimulated astrocytic oxygen consumption by 55% within 30s, whereas this level of glutamate increased DG phosphorylation by only ~60% (Pellerin & Magistretti 1994), i.e., the rise in respiration will generate far more ATP than glycolysis. These findings are supported by many studies that have repeatedly demonstrated that glutamate is oxidized by astrocytes in increasing amounts as extracellular glutamate level rises (McKenna et al. 1996, Dienel 2013, McKenna 2013), consistent with the presence of mitochondria in astrocytic fine processes (Lovatt et al. 2007, Lavialle et al. 2011, Pardo et al. 2011, Derouiche et al. 2015). Recent studies identified macromolecular complexes that support astrocytic glutamate transport and metabolism and showed "
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