Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3

Hruska, Martin; Henderson, Nathan T; Xia, Nan; Marchand, Sylvain J. Le; Dalva, Matthew B.

doi:10.1038/nn.4140

Cited by 50 publications

(74 citation statements)

References 55 publications

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“…How PSD-95 itself docks onto postsynaptic sites has been unclear. Ephrin B3 has been previously implicated in this process (91), although it is unclear if it would be present at high enough levels to mediate postsynaptic anchoring of the highly abundant PSD-95. Instead, postsynaptic anchoring of PSD-95 and, consequently, of AMPARs has been shown to require -actinin, which is highly enriched in spines and binds to the N-terminal 13 residues of PSD-95 (92).…”

Section: Postsynaptic Anchoring Of Ampars By -Actininmentioning

confidence: 99%

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation

et al. 2019

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l-Glutamate is the main excitatory neurotransmitter in the brain, with postsynaptic responses to its release predominantly mediated by AMPA-type glutamate receptors (AMPARs). A critical component of synaptic plasticity involves changes in the number of responding postsynaptic receptors, which are dynamically recruited to and anchored at postsynaptic sites. Emerging findings continue to shed new light on molecular mechanisms that mediate AMPAR postsynaptic trafficking and localization. Accordingly, unconventional secretory trafficking of AMPARs occurs in dendrites, from the endoplasmic reticulum (ER) through the ER-Golgi intermediary compartment directly to recycling endosomes, independent of the Golgi apparatus. Upon exocytosis, AMPARs diffuse in the plasma membrane to reach the postsynaptic site, where they are trapped to contribute to transmission. This trapping occurs through a combination of both intracellular interactions, such as TARP (transmembrane AMPAR regulatory protein) binding to -actinin-stabilized PSD-95, and extracellular interactions through the receptor amino-terminal domain. These anchoring mechanisms may facilitate precise receptor positioning with respect to glutamate release sites to enable efficient synaptic transmission.

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Section: Postsynaptic Anchoring Of Ampars By -Actininmentioning

confidence: 99%

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation

et al. 2019

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“…On neuronal activity, PSD-95 can be recruited to synaptic regions, as observed in the visual cortex after eye opening, which underlies activity-dependent synapse maturation (29,40); however, how activity drives the synaptic transport of PSD-95 during development remains elusive. The synaptic localization of PSD-95 can be regulated by its posttranslational modifications, including phosphorylation and palmitoylation, as well as by molecular binding with ephrin-B3 (10,(41)(42)(43). In this study, using a small interfering peptide that specifically inhibits liprinα1 phosphorylation, we have shown that inhibition of liprinα1 phosphorylation promotes PSD-95 clustering and its synaptic localization through enhanced interaction between these proteins.…”

Section: Discussionmentioning

confidence: 71%

Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

Huang

Lin

Liang

et al. 2017

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

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The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.

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“…To test this, we used a previously described assay in which DIV6-9 neurons are treated with soluble activated ephrin-B2 for 45 min to induce the surface interaction between EphB2 and the NMDAR 13,17,19 . The colocalization of transfected EGFP-GluN1 and endogenous EphB2 was quantified using custom macros 19,45 . Ephrin-B2 activation resulted in clustering of EphB2 in all conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…FRAP analysis. EGFP intensity of bleached puncta and three randomly selected unbleached puncta were quantified for each time point by selecting the regions of interest (ROIs) around selected puncta in every image in the time series 45 . The unbleached puncta served as a control for the photobleaching during acquisition.…”

Section: Methodsmentioning

confidence: 99%

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Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

et al. 2020

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Localization of the N-methyl-D-aspartate type glutamate receptor (NMDAR) to dendritic spines is essential for excitatory synaptic transmission and plasticity. Rather than remaining trapped at synaptic sites, NMDA receptors undergo constant cycling into and out of the postsynaptic density. Receptor movement is constrained by protein-protein interactions with both the intracellular and extracellular domains of the NMDAR. The role of extracellular interactions on the mobility of the NMDAR is poorly understood. Here we demonstrate that the positive surface charge of the hinge region of the N-terminal domain in the GluN1 subunit of the NMDAR is required to maintain NMDARs at dendritic spine synapses and mediates the direct extracellular interaction with a negatively charged phospho-tyrosine on the receptor tyrosine kinase EphB2. Loss of the EphB-NMDAR interaction by either mutating GluN1 or knocking down endogenous EphB2 increases NMDAR mobility. These findings begin to define a mechanism for extracellular interactions mediated by charged domains.

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Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3

Cited by 50 publications

References 55 publications

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation

Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

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