Synaptic frequency decoding by the CaMKII holoenzyme
Description
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.