CaMKII "Autonomy" Is Required for Initiating But Not for Maintaining Neuronal Long-Term Information Storage

Abstract

Ca2ϩ /calmodulin (CaM)-dependent protein kinase II (CaMKII) "autonomy" (T286-autophosphorylation-induced Ca 2ϩ -independent activity) is required for long-term potentiation (LTP) and for learning and memory, as demonstrated by CaMKII T286A mutant mice. The Ͼ20-year-old hypothesis that CaMKII stimulation is required for LTP induction, while CaMKII autonomy is required for LTP maintenance was recently supported using the cell-penetrating fusion-peptide inhibitor antCN27. However, we demonstrate here that ant/ penetratin fusion to CN27 compromised CaMKII-selectivity, by enhancing a previously unnoticed direct binding of CaM to ant/ penetratin. In contrast to antCN27, the improved cell-penetrating inhibitor tatCN21 (5 M) showed neither CaM binding nor inhibition of basal synaptic transmission. In vitro, tatCN21 inhibited stimulated and autonomous CaMKII activity with equal potency. In rat hippocampal slices, tatCN21 inhibited LTP induction, but not LTP maintenance. Correspondingly, tatCN21 also inhibited learning, but not memory storage or retrieval in a mouse in vivo model. Thus, CaMKII autonomy provides a short-term molecular memory that is important in the signal computation leading to memory formation, but is not required as long-term memory store.

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

“…Consistently inhibitors of CaMKII and mutation in the T286 residue blocks specifically the induction of LTP. 83,84 Consistent with these results RNP components are also found to associate with and regulate the translation of CaMKII in a manner required for LTM. 74,85,86 In addition to RBPs, neuronal mRNA translation is regulated by non coding RNAs such as microRNAs (miRNAs) that are abundant in brain tissue.…”

The roles of protein kinases in learning and memory

“…This deficit in memory formation can be partly overcome with repeated training (Yamagata et al 2009). Consistent with this, a peptide derived from an endogenous CaMKII inhibitor, CaMKIIN, that specifically blocks CaMKII activity impairs contextual fear memory formation (Buard et al 2010). An important aspect of aCaMKII activity is that the kinase autophosphorylates at threonine-286 (T286) (for review, see Irvine et al 2006).…”

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

“…The results of this study demonstrate that NO-induced CaMKII autonomy is a novel regulatory mechanism for an enzyme critically involved in mediating synaptic plasticity (1,(3)(4)(5) and ischemic/excitotoxic neuronal cell death (6, 7). Indeed, CaMKII inhibition protected also from neuronal cell death directly induced by NO donors.…”