Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex

Abstract

Memory involves the storage of information at synapses by an LTP-like process. This information storage is synapse specific and can endure for years despite the turnover of all synaptic proteins. There must, therefore, be special principles that underlie the stability of LTP. Recent experimental results suggest that LTP is maintained by the complex of CaMKII with the NMDAR. Here we consider the specifics of the CaMKII/NMDAR molecular switch, with the goal of understanding the biochemical principles that underlie stable information storage by synapses. Consideration of a variety of experimental results suggests that multiple principles are involved. One switch requirement is to prevent spontaneous transitions from the off to the on state. The highly cooperative nature of CaMKII autophosphorylation by Ca2+ (Hill coefficient of 8) and the fact that formation of the CaMKII/NMDAR complex requires release of CaMKII from actin are mechanisms that stabilize the off state. The stability of the on state depends critically on intersubunit autophosphorylation, a process that restores any loss of pT286 due to phosphatase activity. Intersubunit autophosphorylation is also important in explaining why on state stability is not compromised by protein turnover. Recent evidence suggests that turnover occurs by subunit exchange. Thus, stability could be achieved if a newly inserted unphosphorylated subunit was autophosphorylated by a neighboring subunit. Based on other recent work, we posit a novel mechanism that enhances the stability of the on state by protection of pT286 from phosphatases. We posit that the binding of the NMNDAR to CaMKII forces pT286 into the catalytic site of a neighboring subunit, thereby protecting pT286 from phosphatases. A final principle concerns the role of structural changes. The binding of CaMKII to the NMDAR may act as a tag to organize the binding of further proteins that produce the synapse enlargement that underlies late LTP. We argue that these structural changes not only enhance transmission, but also enhance the stability of the CaMKII/NMDAR complex. Together, these principles provide a mechanistic framework for understanding how individual synapses produce stable information storage.

Neonatal Ethanol Exposure Impairs Trace Fear Conditioning and Alters NMDA Receptor Subunit Expression in Adult Male and Female Rats

“…DuPont and colleagues (2014) also reported significant reductions in DH phosphorylated ERK1/2 in 5E rats, which depends on the activation of GluN2B-containing NMDARs (Krapivinsky et al, 2003). NMDAR-gated calcium flux stimulates the translocation and binding of Ca 2+ /calmodulin-dependent protein kinase II to the synaptic GluN2B c-terminus domain, which leads to the activation of plasticity-related signaling molecules essential to LTP maintenance (Lisman and Raghavachari, 2015). Lower synaptic GluN2B expression in 5E rats is proposed to hinder LTP maintenance following TFC, disrupting long-term memory consolidation of the newly learned information.…”

“…Extrasynaptic NMDARs are principally activated under conditions of high glutamate release, which induces opposing effects to synaptic NMDAR activation (Ivanov et al, 2006). As discussed above, synaptic NMDARs play a well-documented role in LTP induction and maintenance (Lisman and Raghavachari, 2015;Lu et al, 2001), and postnatal EtOH is known to inhibit LTP (Puglia and Valenzuela, 2010). Extrasynaptic NMDARs, on the other hand, are thought to dephosphorylate ERK1/2 and promote long-term depression (Ivanov et al, 2006;Liu et al, 2013).…”

Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules

“…It follows that the GluN2B in the matrix gets depleted, keeping the total number of NMDARs constant. The existence of GluN2B in each nanocluster may be functionally important because GluN2B is a critical binding target of phosphorylated CaMKII [27]. The resulting complex (the CaMKII/ NMDAR complex) is critical for the induction [28] and maintenance [29,30] of LTP and may serve as the seed for structural organization of new nanoclusters [27].…”

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

“…Recent work shows that late LTP involves trans-synaptic enlargement of synapses (Bosch et al, 2014; Meyer et al, 2014). Thus a key question for future investigation is to understand how CaMKII could organize this enlargement (for several possibilities, see (Lisman and Raghavachari, 2015)). Furthermore, the elucidation of the fundamental role of CaMKII in memory may serve as a foundation for understanding memory and psychiatric problems in which dysregulation of CaMKII has been observed (Ghosh and Giese, 2015; Robison, 2014).…”