CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory

Neuron. 2016 Oct 5;92(1):75-83. doi: 10.1016/j.neuron.2016.09.002. Epub 2016 Sep 22.


Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARPγ-8, but not TARPγ-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARPγ-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARPγ-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARPγ-8. Together, these findings demonstrate that TARPγ-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.

MeSH terms

  • Animals
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology*
  • Hippocampus / metabolism
  • Learning / physiology*
  • Long-Term Potentiation / physiology*
  • Memory / physiology*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Receptors, AMPA / metabolism


  • Calcium Channels
  • Receptors, AMPA
  • TARP gamma-8 protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2