Role of the CaMKII/NMDA Receptor Complex in the Maintenance of Synaptic Strength

Abstract

During long-term potentiation (LTP), synapses undergo stable changes in synaptic strength. The molecular memory processes that maintain strength have not been identified. One hypothesis is that the complex formed by the Ca2+/Calmodulin -dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) is a molecular memory at the synapse. To establish a molecule as a molecular memory, it must be shown that interfering with the molecule produces a persistent reversal of LTP. We used the CN class of peptides that inhibit CaMKII binding to the NR2B subunit in vitro to test this prediction in rat hippocampal slices. We found that CN peptides can reverse saturated LTP, allowing additional LTP to be induced. The peptide also produced a persistent reduction in basal transmission. We then tested whether CN compounds actually affect CaMKII binding in living cells. Application of CN peptide to slice cultures reduced the amount of CaMKII concentrated in spines, consistent with delocalization of the kinase from a binding partner in the spine. To more specifically assay the binding of CaMKII to the NMDAR, we used coimmunoprecipitation methods. We found that CN peptide decreased synaptic strength only at concentrations necessary to disrupt the CaMKII/NMDAR complex, but not at lower concentrations sufficient to inhibit CaMKII activity. Importantly, both the reduction of the complex and the reduction of synaptic strength persisted after removal of the inhibitor. These results support the hypothesis that the CaMKII/NMDAR complex has switch-like properties that are important in the maintenance of synaptic strength.

The roles of protein kinases in learning and memory

“…In future, it will be interesting to test whether the interaction between the NMDA receptor subunit GluN2B and aCaMKII contribute to memory storage, as this interaction appears to be required for LTP maintenance (Sanhueza et al 2011). In agreement with this idea, point mutations in GluN2B that impair GluN2B/ CaMKII interaction cause a deficit in spatial memory retention, although LTP was not fully blocked and spatial learning was unaffected (Halt et al 2012).…”

Nucleotides and Phosphorylation Bi-directionally Modulate Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Binding to the N-Methyl-d-aspartate (NMDA) Receptor Subunit GluN2B

“…In fact, T286 phosphorylation induced by LTP stimuli may only be very short lived (63). However, a recent study indicated that storage of synaptic memory previously proposed to be mediated by T286 phosphorylation can instead be mediated by the NMDA receptor-bound form of CaMKII (30), and it will be interesting to examine the functional contribution to memory in behavioral studies.…”

Characterization of the Ubiquitin-Modified Proteome Regulated by Transient Forebrain Ischemia

“…22 CaMKII and the NMDA receptor that were found in postischemic insoluble aggregates (Table 1) form a complex that has a role in long-term potentiation. 26 Long-term potentiation is one of the major mechanisms underlying learning and memory. 27 Activity levels of neurons control the postsynaptic composition and signaling by modulating the composition of the postsynaptic density by reversible activation of ubiquitin conjugation/ deconjugation.…”