GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Sylvia Pfennig, Franziska Foss, Diane Bissen, Eva Harde, Julia C. Treeck, Marta Segarra, Amparo Acker-Palmer
Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption of the complex, absence of ApoER2 downstream signaling, and impaired activity-induced and ApoER2-mediated AMPA receptor insertion. Using compound genetics, we show the requirement of this complex for long-term potentiation (LTP). Together, our findings uncover a cooperative ephrinB2 and ApoER2 signaling at the synapse, which serves to modulate activity-dependent AMPA receptor dynamic changes during synaptic plasticity.

Graphical abstract

Teaser

Activity-dependent AMPA receptor dynamic changes modulate synaptic plasticity. Pfennig et al. show that insertion of new AMPA receptors at the synapse is mediated by the formation of a macromolecular complex at the membrane that includes ApoER2, ephrinB2, and AMPA receptors bridged by the multi-PDZ adaptor protein GRIP1.


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