RESUMEN

Activity-dependent remodelling of dendritic spines is essential for neural circuit development and synaptic plasticity, but the precise molecular mechanisms that regulate this process are unclear. Activators of Arp2/3-mediated actin polymerisation are required for spine enlargement; however, during long-term depression (LTD), spines shrink via actin depolymerisation and Arp2/3 inhibitors in this process have not yet been identified. Here, we show that PICK1 regulates spine size in hippocampal neurons via inhibition of the Arp2/3 complex. PICK1 knockdown increases spine size, whereas PICK1 overexpression reduces spine size. NMDA receptor activation results in spine shrinkage, which is blocked by PICK1 knockdown or overexpression of a PICK1 mutant that cannot bind Arp2/3. Furthermore, we show that PICK1-Arp2/3 interactions are required for functional hippocampal LTD. This work demonstrates that PICK1 is a novel regulator of spine dynamics. Via Arp2/3 inhibition, PICK1 has complementary yet distinct roles during LTD to regulate AMPA receptor trafficking and spine size, and therefore functions as a crucial factor in both structural and functional plasticity.

Asunto(s)

Complejo 2-3 Proteico Relacionado con la Actina/antagonistas & inhibidores , Proteínas Portadoras/fisiología , Espinas Dendríticas/fisiología , Plasticidad Neuronal , Proteínas Nucleares/fisiología , Sinapsis/fisiología , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Animales , Animales Recién Nacidos , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Cultivadas , Proteínas del Citoesqueleto , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Embrión de Mamíferos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Tamaño de los Orgánulos/efectos de los fármacos , Tamaño de los Orgánulos/fisiología , ARN Interferente Pequeño/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo