A spatial model of autophosphorylation of CaMKII predicts that the lifetime of phospho-CaMKII after induction of synaptic plasticity is greatly prolonged by CaM-trapping

Thomas Matthew Bartol ^1* Mariam Ordyan ¹ Terrence J Sejnowski ¹ Padmini Rangamani ² Mary B Kennedy ^3,4*

• ¹ Computational Neurobiology Laboratory, Salk Institute, La Jolla, California, United States
• ² Department of Mechanical and Aerospace Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California, United States
• ³ California Institute of Technology, Pasadena, United States
• ⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States

Long-term potentiation (LTP) is a biochemical process that underlies learning in excitatory glutamatergic synapses in the Central Nervous System (CNS). A critical early driver of LTP is autophosphorylation of the abundant postsynaptic enzyme, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). Autophosphorylation is initiated by Ca 2+ flowing through NMDA receptors activated by strong synaptic activity. Its lifetime is ultimately determined by the balance of the rates of autophosphorylation and of dephosphorylation by protein phosphatase 1 (PP1). Here we have modeled the autophosphorylation and dephosphorylation of CaMKII during synaptic activity in a spine synapse using MCell4, an open source computer program for creating particle-based stochastic, and spatially realistic models of cellular microchemistry. The model integrates four earlier detailed models of separate aspects of regulation of spine Ca 2+ and CaMKII activity, each of which incorporate experimentally measured biochemical parameters and have been validated against experimental data. We validate the composite model by showing that it accurately predicts previous experimental measurements of effects of NMDA receptor activation, including high sensitivity of induction of LTP to phosphatase activity in vivo, and persistence of autophosphorylation for a period of minutes after the end of synaptic stimulation. We then use the model to probe aspects of the mechanism of regulation of autophosphorylation of CaMKII that are difficult to measure in vivo. We examine the effects of "CaMtrapping," a process in which the affinity for Ca 2+ /CaM increases several hundred-fold after autophosphorylation. We find that CaM-trapping does not increase the proportion of autophosphorylated subunits in holoenzymes after a complex stimulus, as previously hypothesized. Instead, CaM-trapping may dramatically prolong the lifetime of autophosphorylated CaMKII through steric hindrance of dephosphorylation by protein phosphatase 1. The results provide motivation for experimental measurement of the extent of suppression of dephosphorylation of CaMKII by bound Ca 2+ /CaM. The composite MCell4 model of biochemical effects of complex stimuli in synaptic spines is a powerful new tool for realistic, detailed dissection of mechanisms of synaptic plasticity.