A spatial model of autophosphorylation of CaMKII in a glutamatergic spine suggests a network-driven kinetic mechanism for bistable changes in synaptic strength.

Activation of N-methyl-D-aspartate-type glutamate receptors (NMDARs) at synapses in the CNS triggers changes in synaptic strength that underlie memory formation in response to strong synaptic stimuli. The primary target of Ca2+ flowing through NMDARs is Ca2+/calmodulin-dependent protein kinase II (CaMKII) which forms dodecameric holoenzymes that are highly concentrated at the postsynaptic site. Activation of CaMKII is necessary to trigger long-term potentiation of synaptic strength (LTP), and is prolonged by autophosphorylation of subunits within the holoenzyme. Here we use MCell4, an agent-based, stochastic, modeling platform to model CaMKII holoenzymes placed within a realistic spine geometry. We show how two mechanisms of regulation of CaMKII, 'Ca2+-calmodulin-trapping (CaM-trapping)' and dephosphorylation by protein phosphatase-1 (PP1) shape the autophosphorylation response during a repeated high-frequency stimulus. Our simulation results suggest that autophosphorylation of CaMKII does not constitute a bistable switch. Instead, prolonged but temporary, autophosphorylation of CaMKII may contribute to a biochemical-network-based 'kinetic proof-reading" mechanism that controls induction of synaptic plasticity.