Long-term maintenance and modification of synaptic strength involve the turnover of neurotransmitter receptors. A fundamental mechanism of maintaining and modifying the number of synaptic glutamate receptors is their internalization from the synaptic membrane. AMPA receptors undergo rapid constitutive internalization that is regulated by synaptic activity. For NMDA receptors, constitutive internalization in mature neurons is slow relative to AMPA receptors and not regulated by activity, but is rapid in immature neurons. Although NMDA receptors are thought to be relatively stable during synaptic plasticity, certain stimuli can induce their acute internalization. Mounting evidence suggests that the internalization of glutamate receptors is a primary mechanism of long-term depression (LTD), an electrophysiological paradigm for synaptic plasticity wherein a specific stimulus causes a decrease in synaptic strength. Glutamate receptor internalization is thought to occur through clathrin-mediated endocytosis, a general mechanism for the internalization of proteins from the plasma membrane. However, the specific mechanisms of glutamate receptor internalization are not well understood.

    We found that cpg2 is a splice-variant of the syne-1 gene, a large gene that encodes a protein with an actin-binding domain at the N-terminus and a nuclear transmembrane domain at the C-terminus, separated by a long helical region. The cpg2 transcript is derived from a portion of the separator region, encodes a protein with homologies to dystrophin, and contains motifs predicting a structural function, including several spectrin repeats and coiled-coils. Proteins with these motifs often play a central role in organizing protein complexes. The CPG2 protein specifically localizes to a postsynaptic endocytotic zone of excitatory synapses. RNAi-mediated CPG2 knockdown increases the number of postsynaptic clathrin-coated vesicles, some of which traffic NMDA receptors, disrupts the constitutive internalization of glutamate receptors, and inhibits the activity-induced internalization of synaptic AMPA receptors. Manipulating CPG2 levels also affects dendritic spine size, further supporting a function in regulating membrane transport. Our results suggest that CPG2 is a key component of a specialized postsynaptic endocytic mechanism devoted to the internalization of synaptic proteins, including glutamate receptors. The activity-dependence and distribution of cpg2 expression further suggest that it contributes to the capacity for postsynaptic plasticity inherent to excitatory synapses (Cottrell et al., 2004).