Topological Regulation of Synaptic AMPA Receptor Expression by the RNA-Binding Protein CPEB3

Abstract

Synaptic receptors gate the neuronal response to incoming signals, but they are not homogeneously distributed on dendrites. A spatially defined receptor distribution can preferentially amplify certain synaptic inputs, resize receptive fields of neurons, and optimize information processing within a neuronal circuit. Thus, a longstanding question is how the spatial organization of synaptic receptors is achieved. Here, we find that action potentials provide local signals that influence the distribution of synaptic AMPA receptors along dendrites in mouse cerebellar stellate cells. Graded dendritic depolarizations elevate CPEB3 protein at proximal dendrites, where we suggest that CPEB3 binds to GluA2 mRNA, suppressing GluA2 protein synthesis leading to a distance-dependent increase in synaptic GluA2 AMPARs. The activity-induced expression of CPEB3 requires increased Ca(2+) and PKC activation. Our results suggest a cell-autonomous mechanism where sustained postsynaptic firing drives graded local protein synthesis, thus directing the spatial organization of synaptic AMPARs.

Keywords: AMPA receptor; CPEB3; GluA2; PKC; action potentials; calcium imaging; cerebellar stellate cell; dendritic gradient; subunit composition; topostatic plasticity.