Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport

Filosa, Alessandro; Paixão, Sónia; Honsek, Silke D.; Carmona, Marı́a A.; Becker, Lore; Feddersen, Berend; Gaitanos, Louise; Rudhard, York; Schoepfer, Ralf; Klopstock, Thomas; Kullander, Klas; Rose, Christine R.; Pasquale, Elena B.; Klein, Rüdiger

doi:10.1038/nn.2394

Cited by 254 publications

(228 citation statements)

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“…Through these mechanisms, astrocytes have been proposed to play a critical role in modulating synaptic transmission [9,10], plasticity properties [11][12][13], and longterm potentiation (LTP) [14], consistent with evidence suggesting that astrocytic Ca 2+ transients can occur in spatially restricted areas [15,16]. However, other studies have also proposed different mechanisms to account for a contribution of astrocytes to plasticity and memory [17,18]. Additionally, recent studies also suggest that astrocytes could participate, during development, in the formation of synaptic networks by regulating synaptogenesis [19] and spine pruning [20].…”

Section: Introductionmentioning

confidence: 55%

“…Previous work has suggested that adhesion molecules, by increasing transsynaptic cohesion via N-cadherin [52] or PAP-synapse sticking through EphA4/ephrin-A3 contacts [17,53], could play a role in activity-dependent synapse stability. Here, we propose that PAPs could promote structural interactions and molecular communication between synaptic partners through their reduced motility and increased coverage of the synapse.…”

Section: Discussionmentioning

confidence: 99%

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Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

et al. 2014

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SummaryBackground: Excitatory synapses in the CNS are highly dynamic structures that can show activity-dependent remodeling and stabilization in response to learning and memory. Synapses are enveloped with intricate processes of astrocytes known as perisynaptic astrocytic processes (PAPs). PAPs are motile structures displaying rapid actin-dependent movements and are characterized by Ca 2+ elevations in response to neuronal activity. Despite a debated implication in synaptic plasticity, the role of both Ca 2+ events in astrocytes and PAP morphological dynamics remain unclear. Results: In the hippocampus, we found that PAPs show extensive structural plasticity that is regulated by synaptic activity through astrocytic metabotropic glutamate receptors and intracellular calcium signaling. Synaptic activation that induces long-term potentiation caused a transient PAP motility increase leading to an enhanced astrocytic coverage of the synapse. Selective activation of calcium signals in individual PAPs using exogenous metabotropic receptor expression and two-photon uncaging reproduced these effects and enhanced spine stability. In vivo imaging in the somatosensory cortex of adult mice revealed that increased neuronal activity through whisker stimulation similarly elevates PAP movement. This in vivo PAP motility correlated with spine coverage and was predictive of spine stability. Conclusions: This study identifies a novel bidirectional interaction between synapses and astrocytes, in which synaptic activity and synaptic potentiation regulate PAP structural plasticity, which in turn determines the fate of the synapse. This mechanism may represent an important contribution of astrocytes to learning and memory processes.

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Section: Introductionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

et al. 2014

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“…S3A). EphA4 is involved in the regulation of synaptic plasticity (Murai et al ., 2003; Filosa et al ., 2009), and EphB2 controls both spine formation (Penzes et al ., 2003) and synaptic plasticity (Grunwald et al ., 2001, 2004; Henderson et al ., 2001; Margolis et al ., 2010). Thus, our results suggest that the age‐upregulated miRNAs downregulate the Eph/ephrin signaling pathway involved in synaptic function and plasticity.…”

Section: Resultsmentioning

confidence: 99%

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

et al. 2016

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SummaryHippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age‐associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR‐204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR‐204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR‐204 also decreased the total expression of NR1. miR‐204 induces senescence‐like phenotype in fully matured neurons as evidenced by an increase in p16‐positive cells. We suggest that aging is accompanied by the upregulation of miR‐204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age‐associated decline in hippocampal synaptic plasticity and the related cognitive functions.

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“…Both dendritic spine reduction and AMPA receptor removal are critical factors that contribute to synaptic loss and dysfunction during AD progression (8,27). Another interesting feature of EphA4 is that the receptor is able to trigger reverse signaling in astrocytes via ephrin-A3 and modulate glutamate uptake by lowering glutamate transporters in glial cells (38). It is of interest to determine whether EphA4-ephrin-A3 reverse signaling is involved in synaptic dysfunctions in AD via the dysregulation of glutamate uptake, which has been reported in AD transgenic mice (39).…”

Section: Discussionmentioning

confidence: 99%

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Hung

Huang

et al. 2014

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

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Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a smallmolecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.Abeta | receptor tyrosine kinase | ephrin | drug discovery

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Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport

Cited by 254 publications

References 50 publications

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

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