Modification of AMPA receptor clustering regulates cerebellar synaptic plasticity

Cerebellar long-term depression (LTD) induced at parallel fiber-Purkinje neuron synapses is proposed to underlie certain types of motor learning. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, which mediate chemical transmission in these synapses, are clustered on the postsynaptic membrane. By increasing local density of the receptors, clustering is believed to increase synaptic efficacy. This article focuses on molecular mechanisms regulating the synaptic AMPA receptor clustering in Purkinje cells, which could underlie the expression of cerebellar LTD. Synaptic AMPA receptor clusters in dendritic spines of Purkinje cells are disrupted upon protein kinase C (PKC)-mediated phosphorylation of serine 880 in the C-terminal domain of GluR2. Phosphorylation of this residue causes significant reduction in the affinity of GluR2 C-terminal tail for glutamate receptor interacting protein (GRIP), a molecule known to be crucial for AMPA receptor clustering. Consequently, AMPA receptors on the synaptic membrane are destabilized and internalized by endocytosis. Based on these findings, a model for the expression of cerebellar LTD is proposed, in which a decrease in the number of postsynaptic AMPA receptors, initiated by phosphorylation of GluR2 serine 880, is the major mechanism underlying cerebellar LTD.