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. 2017 Oct 3;21(1):84–96. doi: 10.1016/j.celrep.2017.09.019

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© 2017 The Authors

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMC Copyright notice

ApoER2, GRIP1, and EphrinB2 Genetically Interact at the Synapse

(A–D) ApoER2, GRIP1, and ephrinB2 genetically interact in LTP. ApoER2^+/−; GRIP1^+/− compound mice (A and B) and ApoER2^+/−; efnB2^S-9>A/+ compound mice (C and D) show reduced LTP. LTP was induced by theta burst stimulation (TBS) of Schaffer collaterals and field excitatory postsynaptic potentials (fEPSPs) were recorded in the stratum radiatum of the CA1 region. Representative traces of the compound mice and their respective single-heterozygous and wild-type littermates (+/+) are shown. (ApoER2^+/−; GRIP^+/− in A; ApoER2^+/−; eB2^S9>A/+ in C) LTP is significantly reduced in ApoER2^+/−; GRIP1^+/− compound mice (B) and in ApoER2^+/−; efnB2^S-9>A/+ compound mice (D) compared to their respective control genotypes at 55–60 min after TBS.

(E) GRIP1 regulates ApoER2/ephrinB2 functions at the synapse. Neuronal activity induces ephrinB clustering, leading to the recruitment of Src and its activation, which in turn phosphorylates the adaptor protein Dab1 recruited by ApoER2 receptors. Upon phosphorylation of ephrinB2 in a serine residue (Ser-9), glutamate-receptor-interacting protein 1 (GRIP1) binds to ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors at the synapse in an activity-dependent manner. The formation of such a complex is necessary for activity induced synaptic plasticity.

For (A)–(D), bar graphs show mean ± SEM as calculated across slices (shown as error bars). ApoER2-GRIP1: n = 7 wild-type mice (16 slices), 6 ApoER2^+/− mice (13 slices), 9 GRIP1^+/− mice (16 slices), and 8 ApoER2^+/−; GRIP1^+/− compound mice (21 slices). ApoER2-ephrinB2: n = 6 wild-type mice (13 slices), 4 ApoER2^+/− mice (9 slices), 4 efnB2^S-9>A/+ mice (8 slices), and 6 ApoER2^+/−; efnB2^S-9>A/+ compound mice (15 slices). ^∗p < 0.05; ^∗∗p < 0.01. See also Figure S7.