The ability of neurons to change their responsiveness to synaptic input is a fundamental concept in neuroscience. But although many molecules have been implicated in long-term synaptic plasticity, we have only just begun to work out the ways in which these molecules interact to produce sustained changes in synaptic strength. In a paper published in The Journal of Neuroscience, Perez and colleagues contribute to this effort by showing how PICK1 (protein that interacts with C kinase) might participate in the long-term depression (LTD) of synapses.

There is increasing evidence to suggest that the transport of AMPA-type glutamate receptors in and out of the synaptic membrane is central to activity-dependent changes in synaptic strength. In particular, AMPA receptor endocytosis is thought to contribute to the expression of LTD. In neurons, PICK1 interacts with the AMPA receptor subunit GluR2 by its single PDZ domain. Perez et al. now show, in heterologous cells and in neurons, that PICK1 also interacts directly with protein kinase Cα (PKCα), again by its PDZ domain. But whereas the binding of GluR2 to PICK1 was found to be constitutive, the formation of PICK1–PKCα complexes was dependent on the activation of PKCα, which is thought to expose its PDZ-binding site.

In cultured hippocampal neurons, PICK1 protein expressed alone was distributed throughout the cell. Without 12-O-tetradecanoyl-13-phorbol acetate (TPA), which was used to activate PKC in these experiments, PKCα was also distributed diffusely in neurons. However, in TPA-treated cells, PICK1 strongly colocalized with PKCα in dendritic spines. Likewise, the expression of PICK1 with GluR2 caused these proteins to co-cluster in spines. Perez et al. considered the possibility that PICK1 might promote the PKC phosphorylation of GluR2 in these clusters. They found that phosphorylated GluR2 was abundant in the dendrites of TPA-treated cells compared with untreated controls, and strongly colocalized with PICK1 in spines. Finally, they showed that the PDZ-dependent association of PICK1 with GluR2 significantly reduced the plasma membrane levels of this receptor subunit.

On the basis of these findings, the authors propose that PICK1 targets activated PKCα to dendritic spines, where it phosphorylates GluR2, releasing AMPA receptors from the synaptic anchoring proteins GRIP (glutamate-receptor-interacting protein) and ABP, and allowing the PICK1-dependent removal of GluR2 from the synaptic membrane. These studies highlight the important role of PICK1 in the activity-dependent endocytosis of AMPA receptors.

The expression of LTD has been studied in the both the cerebellum and hippocampus; it will be interesting to learn whether similar mechanisms underlie AMPA receptor endocytosis in these areas.