Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity

Abstract

Synaptic cadherin adhesion complexes are known to be key regulators of synapse plasticity. However, the molecular mechanisms that coordinate activity-induced modifications in cadherin localization and adhesion and subsequent changes in synapse morphology and efficacy, remain unanswered. We demonstrate that the intracellular cadherin binding protein, δ-catenin, is transiently palmitoylated by DHHC5 following enhanced synaptic activity, and that palmitoylation increases δ-catenin/cadherin interactions at synapses. Both the palmitoylation of δ-catenin and its binding to cadherin are required for activity-induced stabilization of N-cadherin at synapses, the enlargement of postsynaptic spines, as well as insertion of GluA1 and GluA2 subunits into the synaptic membrane and the concomitant increase in mEPSC amplitude. Importantly, context-dependent fear conditioning in mice results in increased δ-catenin palmitoylation as well as increased δ-catenin/cadherin associations at hippocampal synapses. Together, this suggests a role for palmitoylated δ-catenin in coordinating activity-dependent changes in synaptic adhesion molecules, synapse structure, and receptor localization that are involved in memory formation.

δ-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions

“…Our results are consistent with data (27) that demonstrate that knockdown of ␦-catenin leads to a reduction in the activity induced stability of cadherin. Furthermore, Brigidi et al (27) demonstrated that knockdown of ␦-catenin perturbs chemically induced LTP-induced alterations in spine architecture in a cadherin-dependent manner.…”

“…Furthermore, Brigidi et al (27) demonstrated that knockdown of ␦-catenin perturbs chemically induced LTP-induced alterations in spine architecture in a cadherin-dependent manner. Our data demonstrate that the reduction in head width and length induced by knockdown of ␦-catenin is independent of alterations in neural network activity.…”

“…All constructs of ␦-catenin have been previously described (26). The EGFP 3 -␦-catenin and K581M* constructs of ␦-catenin were a kind gift from Dr. Shernaz Bamji (University of British Columbia) (27). EGFP-␦-catenin represents the XM_006520032.1.…”

“…To further examine this cooperation, we took advantage of a point mutation in ␦-catenin, K581M* (Fig. 7c), which has been demonstrated to significantly abolish its interaction with N-cadherin (27). Primary rat cultured neurons were transfected with vector or shRNA or shRNA plus ␦-catenin-K581M* at DIV 11-12.…”

Palmitoylation of plakophilin is required for desmosome assembly

“…Delta-catenin has been shown to be palmitoylated in cultured hippocampal neurons, and disruption of the palmitoylation of delta-catenin decreases its association with N-cadherin. Interestingly, these authors identified two cysteines (C960 and C961) that are palmitoylated by the PAT DHHC5 (Brigidi et al, 2014). These cysteines are distinct from the conserved cysteine that we have identified in the plakophilins.…”