Prevention of long-term memory loss after retrieval by an endogenous CaMKII inhibitor

Abstract

CaMK2N1 and CaMK2N2 are endogenous inhibitors of calcium/calmodulin-dependent protein kinase II (CaMKII), a key synaptic signaling molecule for learning and memory. Here, we investigated the learning and memory function of CaMK2N1 by knocking-down its expression in dorsal hippocampus of mice. We found that reduced CaMK2N1 expression does not affect contextual fear long-term memory (LTM) formation. However, we show that it impairs maintenance of established LTM, but only if retrieval occurs. CaMK2N1 knockdown prevents a decrease of threonine-286 (T286) autophosphorylation of αCaMKII and increases GluA1 levels in hippocampal synapses after retrieval of contextual fear LTM. CaMK2N1 knockdown can also increase CaMK2N2 expression, but we show that such increased expression does not affect LTM after retrieval. We also found that substantial overexpression of CaMK2N2 in dorsal hippocampus impairs LTM formation, but not LTM maintenance, suggesting that CaMKII activity is not required for LTM storage. Taken together, we propose a specific function for CaMK2N1; enabling LTM maintenance after retrieval by inhibiting T286 autophosphorylation of αCaMKII.

Calcium/calmodulin‐dependent kinase II and memory destabilization: a new role in memory maintenance

“…Vigil et al . () supports the role of CaMK2N1 as a physiological mechanism by which CaMKII‐induced memory destabilization can be controlled. Additionally, reduction in CaMKII S331 phosphorylation could be responsible for initiating CaMKII‐induced memory destabilization (Rich et al .…”

“…Vigil et al . () and Cao et al . () report the occurrence of a retrieval‐induced memory erasure, but lack the direct link with a biological marker of memory destabilization.…”

“…Additionally, contextual fear memory retrieval promotes CaMK2N1 expression in dorsal hippocampi (Vigil et al . ). If CaMKII activation induces memory destabilization, CaMK2N1 expression could be induced by memory retrieval to control the destabilization process.…”

“…Corroborating with this hypothesis, we have recently reported a contextual fear memory retrieval‐induced hippocampal expression of CaMK2N1, and this expression was necessary for memory maintenance after retrieval (Vigil et al . ). CaMK2N1 is known to block CaMKII binding to GluN2B (Vest et al .…”

“…This hypothesis could explain the observations of Vigil et al . (). Once memory is retrieved, Ca MKII increases GluN2B localization within the synapse, starting a memory destabilization process.…”