cpg2 encodes a brain- and synapse-specific protein that regulates the endocytosis of glutamate receptors

Abstract

Synaptic plasticity is the rearrangement of neuronal connections that likely underlies learning and memory. It requires the expression of a set of genes essential for the synaptic changes that occur during plasticity, candidate plasticity gene 2 (cpg2) was isolated in a screen for genes that effect synaptic plasticity. In this thesis, I analyze the regulation and function of cpg2 in neurons. I find that cpg2 is a splice-variant of the syne-1 gene that is expressed only in brain regions capable of plasticity and encodes a protein specifically localized to a postsynaptic endocytic zone of excitatory synapses, often in the vicinity of clathrin-coated pits. I further show that, through its C-terminal coiled-coil motifs, CPG2 binds to the actin cytoskeleton and to endophilin B2, a member of a family of proteins involved in membrane trafficking. RNAi-mediated knock-down of CPG2 increased the number of postsynaptic clathrin-coated vesicles, some of which trafficked NMDA receptors, and disrupted the internalization of glutamate receptors. In addition, alterations in its protein levels affected dendritic spine size, supporting a role for CPG2 in regulating membrane trafficking. These data suggest that CPG2 organizes a network of proteins at the postsynaptic endocytic zone critical for glutamate receptor internalization. Due to its unique expression profile and subcellular localization, CPG2 may underlie a novel adaptation of the clathrin-mediated endocytosis pathway that enables the capacity for postsynaptic plasticity in excitatory synapses.