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 theAMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKIImediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by autonomous'' CaMKII was further stimulated by Ca-2+/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.