Aoto J, Chen L.. Bidirectional ephrin/Eph signaling in synaptic functions. Brain Res 1184: 72-80

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
Brain Research (Impact Factor: 2.84). 01/2008; 1184(1):72-80. DOI: 10.1016/j.brainres.2006.11.033
Source: PubMed


Eph receptors, the largest family of receptor tyrosine kinases, and their membrane bound ligands, the ephrins, are involved in multiple developmental and adult processes within and outside of the nervous system. Bi-directional signaling from both the receptor and the ligand is initiated by ephrin-Eph binding upon cell-cell contact, and involves interactions with distinct subsets of downstream signaling molecules related to specific functions. In the CNS, Ephs and ephrins act as attractive/repulsive, migratory and cell adhesive cues during development and participate in synaptic functions in adult animals. In this review, we will focus on recent findings highlighting the functions of ephrin/Eph signaling in dendritic spine morphogenesis, synapse formation and synaptic plasticity.

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Available from: Jason Aoto, May 05, 2015
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    • "Furthermore, the ephrin system may also play important action on neurorestoration, remarkably in the lesioned spinal cord, due to its actions on multiple cellular regenerative events. For instance, ephrins could modulate axonal guidance [21–23], target reinnervation, synaptic plasticity [24–26], neurotrophic factor signaling-induced neuroprotection/neuroplasticity, and endothelial/glial reaction-induced wound repair [27–29]. The large range of actions of ephrin system is favored by the spread distribution of the receptor tyrosine kinase Eph and its membrane-bound ligand ephrin in astrocytes, endothelial cells as well as in presynaptic and postsynaptic neurons [30–32]. "
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    ABSTRACT: Pigment epithelium derived factor (PEDF) exerts trophic actions to motoneurons and modulates nonneuronal restorative events, but its effects on neuroplasticity responses after spinal cord (SC) injury are unknown. Rats received a low thoracic SC photothrombotic ischemia and local injection of PEDF and were evaluated behaviorally six weeks later. PEDF actions were detailed in SC ventral horn (motor) in the levels of the lumbar central pattern generator (CPG), far from the injury site. Molecules related to neuroplasticity (MAP-2), those that are able to modulate such event, for instance, neurotrophic factors (NT-3, GDNF, BDNF, and FGF-2), chondroitin sulfate proteoglycans (CSPG), and those associated with angiogenesis and antiapoptosis (laminin and Bcl-2) and Eph (receptor)/ephrin system were evaluated at cellular or molecular levels. PEDF injection improved motor behavioral performance and increased MAP-2 levels and dendritic processes in the region of lumbar CPG. Treatment also elevated GDNF and decreased NT-3, laminin, and CSPG. Injury elevated EphA4 and ephrin-B1 levels, and PEDF treatment increased ephrin A2 and ephrins B1, B2, and B3. Eph receptors and ephrins were found in specific populations of neurons and astrocytes. PEDF treatment to SC injury triggered neuroplasticity in lumbar CPG and regulation of neurotrophic factors, extracellular matrix molecules, and ephrins.
    Neural Plasticity 07/2014; 2014(21):451639. DOI:10.1155/2014/451639 · 3.60 Impact Factor
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    • "The most prominent central effects were observed in the double ephrin - A2A5 – / – mice , presumably because of re - dundancy within the ephrin - A family . For example , EphA2 – EphA8 receptors are capable of binding to all ephrin - A proteins [ Aoto and Chen , 2007 ] . "
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    ABSTRACT: Eph receptors and ephrin ligands are large families of cell surface proteins which have established roles in axonal growth and guidance. These are well characterized in the visual and somatosensory systems but are less well documented in the auditory pathway. We examined the possible functional role of two ephrin genes (ephrin-A2 and ephrin-A5) in the auditory system by measuring auditory brainstem responses (ABR) to tone bursts from 6 to 30 kHz in ephrin-A2(-/-), ephrin-A5(-/-) and ephrin-A2A5(-/-) (knockout) mice. At high frequencies, the ephrin-A2A5(-/-) mice exhibited thresholds that were significantly lower than in wild-type mice by approximately 20 dB, suggesting ephrin-A2 and ephrin-A5 may have frequency-specific effects on the auditory system. There were also alterations in ABR wave peak amplitudes that were specific to each mouse strain which suggested both peripheral and central involvement of EphA-ephrin-A signalling in auditory function. © 2014 S. Karger AG, Basel.
    Audiology and Neurotology 01/2014; 19(2-2):115-126. DOI:10.1159/000357029 · 1.71 Impact Factor
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    • "Ephrins and their Eph receptors are attractive candidates for modulating structural plasticity of synapses, because of their synaptic expression and ability to coordinate contact-mediated bidirectional signaling in ligand-and receptor-containing cells (Aoto and Chen, 2007; Klein, 2009; Lai and Ip, 2009; Murai and Pasquale, 2004). Based on their cell membrane attachment and binding preference to Eph receptors, ephrins are classified into two groups: (1) GPI-linked ephrin-As that preferentially interact with EphA receptors and (2) transmembrane ephrin-Bs that preferentially bind to EphB receptors. "
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    ABSTRACT: Refinement of mammalian neural circuits involves substantial experience-dependent synapse elimination. Using in vivo two-photon imaging, we found that experience-dependent elimination of postsynaptic dendritic spines in the cortex was accelerated in ephrin-A2 knockout (KO) mice, resulting in fewer adolescent spines integrated into adult circuits. Such increased spine removal in ephrin-A2 KOs depended on activation of glutamate receptors, as blockade of the N-methyl-D-aspartate (NMDA) receptors eliminated the difference in spine loss between wild-type and KO mice. We also showed that ephrin-A2 in the cortex colocalized with glial glutamate transporters, which were significantly downregulated in ephrin-A2 KOs. Consistently, glial glutamate transport was reduced in ephrin-A2 KOs, resulting in an accumulation of synaptic glutamate. Finally, inhibition of glial glutamate uptake promoted spine elimination in wild-type mice, resembling the phenotype of ephrin-A2 KOs. Together, our results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex.
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