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

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. •CaMKIIα phosphorylates TARPγ-8 directly at S277 and S281•TARPγ-8 phosphorylation at CaMKIIα sites is enhanced during chemical LTP•CaMKIIα enhances AMPAR-mediated transmission via TARPγ-8 phosphorylation sites•CaMKIIα phosphorylation of TARPγ-8 is required for LTP and learning and memory Park et al. report hippocampus-enriched TARPγ-8 as a critical CaMKIIα substrate for LTP and learning and memory. LTP increases TARPγ-8 phosphorylation, and this phosphorylation is required for CaMKII-dependent increase of AMPAR-mediated transmission, LTP, and fear conditioning.