Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation

Abstract

Trafficking of AMPA receptors is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. Here, we identified a direct interaction between NSF, an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Plk2, an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adapter proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a novel motif within Plk2 independent from canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons

“…A previous study has reported that, in COS-7 cells, chronic overexcitation impaired homeostatic synaptic plasticity by decreasing AMPA receptor expression (66). Indeed, decreased expression of tyrosine hydroxylase and dopamine ␤ hydroxylase is known to occur in LC neurons of Mecp2-null mice, leading to insufficient NE biosynthesis (5,67).…”

Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2

“…This is consistent with previous studies in which manipulations of proteins that interact with the AMPAR endocytic machinery were shown to perturb the steady-state number of AMPAR at synaptic sites (26). CPG2 function may have particular significance in the context of synaptic plasticity, because regulated AMPAR internalization plays a critical role in several forms of synaptic plasticity, including LTD (27,28) and homeostatic synaptic down-scaling (29).…”

Plk2 Raps up Ras to subdue synapses

“…Clearly, Plk2 controls multiple pathways beyond small GTPases, 41 and understanding the interplay of these pathways with each other and with other known homeostatic proteins such as Arc will be of importance Figure 2. Microdomains of ras/rap signaling mediated by GaPs/GEFs.…”