Synaptic frequency decoding by the CaMKII holoenzyme

Synaptic frequency decoding underlies higher brain functions and has been tightly linked to CaMKII autophosphorylation at T286 (pT286). However, pT286 mediates both long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity that are induced by different frequencies. We show that the frequency decoding in the LTP- versus LTD-decision is instead mediated by the inhibitory CaMKII autophosphorylation at T305/306 (pT305/306). This phosphorylation also determined CaMKII movement to excitatory versus inhibitory synapses after LTP- versus LTD-stimuli. Thereby, pT305/306 communicated excitatory LTD-stimuli to inhibitory synapses, where it increased GABAA-receptor surface expression. Within the 12meric CaMKII holoenzymes, fast pT305/306 required prior pT286 and then curbed CaMKII activity by two mechanisms: (i) a cis-subunit reaction reduced both Ca2+-stimulation and autonomous activity, and (ii) a trans-subunit reaction enabled complete activity shut-down and feed forward inhibition of further pT286. These are surprising fundamental additions to the long-studied CaMKII regulation and function in neuronal plasticity.