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

Sci Rep. 2017 Jun 22;7(1):4040. doi: 10.1038/s41598-017-04355-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Fear
  • Gene Expression
  • Gene Knockdown Techniques
  • Hippocampus / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Memory, Long-Term*
  • Mice
  • Phosphorylation
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Receptors, AMPA / metabolism


  • Camk2n2 protein, mouse
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, AMPA
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • glutamate receptor ionotropic, AMPA 1