Molecular Switches at the Synapse Emerge from Receptor and Kinase Traffic

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Abstract
Changes in the synaptic connection strengths between neurons are believed to play a role in memory formation. An important mechanism for changing synaptic strength is through movement of neurotransmitter receptors and regulatory proteins to and from the synapse. Several activity-triggered biochemical events control these movements. Here we use computer models to explore how these putative memory-related changes can be stabilised long after the initial trigger, and beyond the lifetime of synaptic molecules. We base our models on published biochemical data and experiments on the activity-dependent movement of a glutamate receptor, AMPAR, and a calcium-dependent kinase, CaMKII. We find that both of these molecules participate in distinct bistable switches. These simulated switches are effective for long periods despite molecular turnover and biochemical fluctuations arising from the small numbers of molecules in the synapse. The AMPAR switch arises from a novel self-recruitment process where the presence of sufficient receptors biases the receptor movement cycle to insert still more receptors into the synapse. The CaMKII switch arises from autophosphorylation of the kinase. The switches may function in a tightly coupled manner, or relatively independently. The latter case leads to multiple stable states of the synapse. We propose that similar self-recruitment cycles may be important for maintaining levels of many molecules that undergo regulated movement, and that these may lead to combinatorial possible stable states of systems like the synapse. One of the key cellular changes that accompanies memory formation is a change in the efficacy of synaptic connections between nerve cells. Such changes may arise from long-lasting changes in the number of receptor ion channels at the synapse, and also from changes in their conductance. The authors ask how the cell maintains these changes despite molecular turnover, traffic, and biochemical noise. They use computer simulations as an “in silico” microscope to extrapolate biochemical and light microscopy measurements down to sub-synaptic volumes. Based on these computer models, the authors propose that there is a self-sustaining switch involving the movement of receptors (AMPA receptors) to and from the synaptic membrane. The switch works because the presence of sufficient receptors at the membrane biases the trafficking machinery to recruit still more receptors. This switch has suggestive parallels with experimental observations of the conversion of synapses from silent to active, which involves AMPA receptor insertion. The authors show that yet more conductance states may arise through interactions with a biochemical switch involving a synaptic kinase (CaMKII). This receptor switch illustrates how the cell may harness molecular turnover and traffic to maintain, rather than wash out, cellular structures and states.