RESUMEN
Drugs of abuse alter synaptic connections in the reward circuitry of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation in the ventral tegmental area and is recruited to the synaptic membranes of excitatory synapses onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.
Asunto(s)
Cadherinas/fisiología , Cocaína/farmacología , Condicionamiento Psicológico/fisiología , Plasticidad Neuronal/fisiología , Área Tegmental Ventral/fisiología , Animales , Cadherinas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Receptores AMPA/metabolismo , Sinapsis/fisiología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
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 the subsequent changes in synapse morphology and efficacy remain unknown. We demonstrate that the intracellular cadherin binding protein δ-catenin is transiently palmitoylated by DHHC5 after 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 and the enlargement of postsynaptic spines, as well as the insertion of GluA1 and GluA2 subunits into the synaptic membrane and the concomitant increase in miniature excitatory postsynaptic current amplitude. Notably, context-dependent fear conditioning in mice resulted in increased δ-catenin palmitoylation, as well as increased δ-catenin-cadherin associations at hippocampal synapses. Together these findings suggest 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.