Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling

Murai, Keith K.; Nguyen, Louis N.; Irie, Fumitoshi; Yamaguchi, Yu; Pasquale, Elena B.

doi:10.1038/nn994

Cited by 460 publications

(477 citation statements)

References 41 publications

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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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Section: Resultsmentioning

confidence: 99%

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

et al. 2016

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“…4e-f). In contrast, knockdown of EphrinA3, a CAM with known roles in astrocyte-neuron interactions 22 , did not alter astrocyte morphogenesis (Extended Data Fig. 4g-h).…”

Section: Astrocytes Require Nls For Complexitymentioning

confidence: 90%

“…g , Representative images of transfected astrocytes (green) with shCtrl or an shRNA against EphrinA3 (EFNA3) in co-culture with neurons (not visible). EFNA3 is a CAM expressed in astrocytes that regulates astrocyte-synapse interactions in the hippocampus 22 . h , Sholl quantification of astrocyte complexity in shCtrl and shEFNA3-transfected astrocytes in co-culture with neurons.…”

Section: Extended Datamentioning

confidence: 99%

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

Stogsdill

Ramirez

Liu

et al. 2017

Nature

380

413

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Astrocytes are highly complex glial cells with numerous fine cellular processes which infiltrate the neuropil to interact with synapses. The mechanisms controlling the establishment of astrocytes’ remarkable morphology and how impairing astrocytic infiltration of the neuropil alters synaptic connectivity are largely unknown. Here we find that cortical astrocyte morphogenesis depends on direct contact with neuronal processes and occurs in tune with the growth and activity of synaptic circuits. Neuroligin (NL) family cell adhesion proteins, NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, cortical excitatory synapse formation and function is diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a novel mechanism of action for NLs and link astrocyte morphogenesis to synaptogenesis. Because NL mutations are implicated in various neurological disorders, these findings also offer an astrocyte-based mechanism of neural pathology.

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“…One of the most studied adhesion molecules that could be involved in direct signaling between astrocytes and neurons has been EphA4 (Carmona et al, 2009; Filosa et al, 2009; Murai and Pasquale, 2004; Tremblay et al, 2009). This receptor tyrosine kinase is located in dendritic spines, and its ligand ephrin‐A3 is enriched in PAP membranes (Murai et al, 2003). Binding of the two molecules is important for normal spine morphology (Murai et al, 2003) and mitigating the contact leads to unstable spines (Nishida and Okabe, 2007).…”

Section: Molecular Machineries Of Astroglial Morphogenesis: Cytoskelementioning

confidence: 99%

“…This receptor tyrosine kinase is located in dendritic spines, and its ligand ephrin‐A3 is enriched in PAP membranes (Murai et al, 2003). Binding of the two molecules is important for normal spine morphology (Murai et al, 2003) and mitigating the contact leads to unstable spines (Nishida and Okabe, 2007). Furthermore, the binding of exogenous and endogenous ephrin‐A to astrocytic EphA ligands mediates astrocyte process outgrowth (Nestor et al, 2007).…”

Section: Molecular Machineries Of Astroglial Morphogenesis: Cytoskelementioning

confidence: 99%

Morphological plasticity of astroglia: Understanding synaptic microenvironment

Heller

Rusakov

2015

Glia

132

137

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Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecular machinery on the scale of nanoscopic astroglial compartments remains a challenge. Here we briefly summarize the current knowledge regarding the cellular organisation of astroglia in the synaptic microenvironment and discuss molecular mechanisms potentially involved in use‐dependent astroglial morphogenesis. We also discuss recent observations concerning morphological astroglial plasticity, the respective monitoring methods, and some of the newly emerging techniques that might help with conceptual advances in the area. GLIA 2015;63:2133–2151

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Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling

Cited by 460 publications

References 41 publications

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

Morphological plasticity of astroglia: Understanding synaptic microenvironment

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