Autonomous CaMKII Mediates Both LTP and LTD Using a Mechanism for Differential Substrate Site Selection

Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced “autonomous” (Ca2+-independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by “autonomous” CaMKII was further stimulated by Ca2+/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference. [Display omitted] •Autonomous CaMKII activity is required not only for LTP, but also for LTD•LTP stimuli (strong but brief) favor traditional substrate site phosphorylation•LTD stimuli (weak but prolonged) instead favor a distinct substrate class•Deciding factor in substrate choice is further Ca2+/CaM stimulation of CaMKII CaMKII and its “autonomous” activity, induced by T286-autophosphorylation, is a crucial mediator of long-term potentiation (LTP) of synaptic strength. In this study, Dell’Acqua, Bayer, and colleagues show that this CaMKII autonomy is also required for long-term depression (LTD), an opposing form of synaptic plasticity. These opposing functions involve stimulus-dependent differential substrate site selection on GluA1: S831 (a traditional substrate favored by LTP-type stimuli) versus S567 (a distinct substrate class instead favored by LTD-type stimuli).