The CaMKII/NMDAR complex as a molecular memory

Abstract

CaMKII is a major synaptic protein that is activated during the induction of long-term potentiation (LTP) by the Ca2+ influx through NMDARs. This activation is required for LTP induction, but the role of the kinase in the maintenance of LTP is less clear. Elucidating the mechanisms of maintenance may provide insights into the molecular processes that underlie the stability of stored memories. In this brief review, we will outline the criteria for evaluating an LTP maintenance mechanism. The specific hypothesis evaluated is that LTP is maintained by the complex of activated CaMKII with the NMDAR. The evidence in support of this hypothesis is substantial, but further experiments are required, notably to determine the time course and persistence of complex after LTP induction. Additional work is also required to elucidate how the CaMKII/NMDAR complex produces the structural growth of the synapse that underlies late LTP. It has been proposed by Frey and Morris that late LTP involves the setting of a molecular tag during LTP induction, which subsequently allows the activated synapse to capture the proteins responsible for late LTP. However, the molecular processes by which this leads to the structural growth that underlies late LTP are completely unclear. Based on known binding reactions, we suggest the first molecularly specific version of tag/capture hypothesis: that the CaMKII/NMDAR complex, once formed, serves as a tag, which then leads to a binding cascade involving densin, delta-catenin, and N-cadherin (some of which are newly synthesized). Delta-catenin binds AMPA-binding protein (ABP), leading to the LTP-induced increase in AMPA channel content. The addition of postsynaptic N-cadherin, and the complementary increase on the presynaptic side, leads to a trans-synaptically coordinated increase in synapse size (and more release sites). It is suggested that synaptic strength is stored stably through the combined actions of the CaMKII/NMDAR complex and N-cadherin dimers. These N-cadherin pairs have redundant storage that could provide informational stability in a manner analogous to the base-pairing in DNA.

The roles of protein kinases in learning and memory

“…Finally, regarding memory storage, it is appealing to think of a perpetuating kinase mechanism that persistently keeps synapses in an activated state and that overcomes molecular turnover (Crick 1984;Lisman 1985). Accordingly, the current candidate kinases for memory storage are CaMKII (interacting with the NMDA receptor) (Sanhueza and Lisman 2013) and PKC isoforms that have no regulatory domains and that are locally translated (Glanzman 2013).…”

“…For mechanisms of memory storage it is important that the signaling perpetuates beyond molecular turnover (Crick 1984;Lisman 1985). Recently, a model has been proposed as to how GluN2B/aCaMKII signaling may persist by providing anchoring sites for AMPA receptors (Sanhueza and Lisman 2013). Another point of future investigations concerns the complex regulation of CaMKII activity.…”

Enzymatic Activity of CaMKII Is Not Required for Its Interaction with the Glutamate Receptor Subunit GluN2B

“…Ca 21 /Calmodulin (CaM)-dependent protein kinase II (CaM-KII) and the N-methyl-D-aspartate-type glutamate receptor (NMDAR) are important mediators of long-term potentiation (LTP) (for review see Coultrap and Bayer, 2012a;Sanhueza and Lisman, 2013). During an LTP stimulus, CaMKII becomes activated, resulting in an increase of AMPA-type glutamate receptor (AMPAR) conductance (Derkach et al, 1999;Kristensen et al, 2011) and synaptic localization (Hayashi et al, 2000;Opazo et al, 2010).…”

Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation

“…Indeed, it inhibits the autophosphorylation of a secondary site (Thr 305) which would precisely be responsible for the kinase deactivation and release from synapses (Shen et al 2000). Besides its functional role, the binding of CaMKII to NMDA receptors has structural consequences as well, as it creates scaffolding for AMPA receptor-binding proteins and allows subsequent incorporation of additional AMPA receptors into the PSD (Lisman and Zhabotinsky 2001;Sanhueza and Lisman 2013). Sanhueza et al (2011) showed that the CN class of peptides inhibiting CaMKII binding to NR2B reduced basal synaptic transmission and reversed saturated LTP.…”