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.

Figure 1

TatCN21 reverses LTP. fEPSPs recorded from the CA1 region of a hippocampal slice. At 20 min, LTP was induced by four tetani. This LTP was saturated, as evidenced by lack of further potentiation when an additional tetanus was given at 40 min. tatCN21 was then applied for 30 min. Upon removal, there was partial recovery, but also a non-recoverable component that demonstrates LTP reversal. To verify that saturated LTP had indeed been reversed, an additional tetanus was given (right), and this reinduced LTP. In control experiments without tatCN21 application, LTP could not be reinduced.

Figure 2

Working hypothesis for how formation of CaMKII/NMDAR complex during LTP induction leads to subsequent binding reactions necessary for late LTP. A, Before LTP induction (some NMDA channels have no CaMKII bound). B, During LTP induction, CaMKII is activated and forms a persistent complex with the NMDA channel, thus forming a tag. C, This serves as a structural seed for the gradual capture of densin, delta-catenin, ABP, and N-cadherin (cad). The addition of ABP provides additional anchoring sites for AMPA channels, thereby strengthening transmission. The binding of additional N-cadherin (which is synthesized in response to activity) enlarges the synapse both presynaptically and postsynaptically.

Figure 3

Model of trans-synaptic growth. Presynaptic (red) and postsynaptic (blue) cadherins (C) form homophilic bonds in the synaptic cleft (analogous to base-pairing in DNA). Cadherins are crosslinked by proteins in the postsynaptic density and presynaptic grid (yellow, orange), including CaMKII (red hexagons), which are analogous to the backbone of the DNA strands. Middle 2-D picture emphasizes analogy to DNA. Synapse size and strength are determined by the number of N-cadherin dimers. This number is redundantly stored by presynaptic and postsynaptic cadherin arrays and increases during late LTP.