Synaptic plasticity: the subcellular location of CaMKII controls plasticity

In a neuron's dendritic spine, the location of CaMKII is controlled by a number of interacting factors, including its ability to bind calcium/calmodulin, its phosphorylation state and the synthesis of new subunits in the dendrites.New studies have shown that the exact location of CaMKII is crucial for the form and endurance of synaptic plasticity. Our concept of the synapse and synaptic function has evolved enormously over the past decade. In the past, the synapse has often been treated as a system of complicated switches turned on and off by endogenous transmitters and pharmacological agents. More recently, however, an understanding of what lies beneath the membrane on either side of a synapse has led to a view of synaptic function as the operation of an intricate set of molecular mechanisms. The synaptic machine even has real moving parts: AMPA and NMDA glutamate receptors have been shown to slot in and out of the membrane 1. and 2.; and calcium/calmodulin kinase II (CaMKII) has been shown to move in and out of the “post-synaptic density” – the specialised region immediately beneath the postsynaptic neuron's membrane that faces the synaptic cleft – under the control of its own phosphorylation state [3]. Understanding the role of various synaptic constituents therefore relies, not only on knowing how they are activated and what they act upon, but also where they are located within the molecular machinery at any one time. Two groups 4. and 5. have now reported on the functional significance of the regulated subcellular location of CaMKII in dendrites. Elgersma et al. [4] have studied the importance of CaMKII located in the postsynaptic density. And Miller et al. [5] have looked at the significance of CaMKII mRNA translation in the dendrites – as opposed to the soma – by preventing the delivery of CaMKII mRNA to the dendrites. Using advanced molecular genetic techniques, both groups have shown that the location of CaMKII can determine its function and thereby affect the plasticity of the synapse. In its basal state, CaMKII is phosphorylated on residue threonine 305 [6]. Elgersma et al. [4] found that phosphorylation at this site substantially decreases the amount of CaMKII in the post-synaptic density [4]. They replaced CaMKII's threonine 305 with an aspartate – mutation T305D – which mimics a phosphorylation group. They found that this led to a reduction in the total amount of CaMKII in post-synaptic-density-enriched fractions to only 28% of the wild-type level. This is consistent with earlier studies which showed that preventing phosphorylation at the 305/306 sites increases CaMKII's affinity for the post-synaptic density [3]. The explanation for this behaviour is probably that phosphorylation at the inhibitory 305 site prevents binding of calcium/calmodulin to CaMKII and, as such binding is necessary for translocation of CaMKII to the post-synaptic density, the lack of it leads to CaMKII being marooned in the cytoplasm ( Figure 1)