Dendritic spine neck plasticity controls synaptic expression of long-term potentiation

Abstract Dendritic spines host glutamatergic excitatory synapses and compartmentalize biochemical signalling underlying synaptic plasticity. The narrow spine neck that connects the spine head with its parent dendrite is the crucial structural element of this compartmentalization. Both neck morphology and its molecular composition differentially regulate exchange of molecular signals between the spine and rest of the neuron. Although these spine neck properties themselves show activity-dependent plasticity, it remains unclear what functional role spine neck plasticity plays in synaptic plasticity expression. To address this, we built a data-constrained biophysical computational model of AMPA receptor (AMPAR) trafficking and intracellular signalling involving Ca 2+ /calmodulin-dependent kinase II (CaMKII) and the phosphatase calcineurin in hippocampal CA1 neurons, which provides new mechanistic insights into spatiotemporal AMPAR dynamics during long-term potentiation (LTP). Using the model, we tested how plasticity of neck morphology and of neck septin7 barrier, which specifically restricts membrane protein diffusion, affect LTP. We found that spine neck properties control LTP by regulating the balance between AMPAR and calcineurin escape from the spine. Neck plasticity that increases spine-dendrite coupling reduces LTP by allowing more AMPA receptors to diffuse away from the synapse. Surprisingly, neck plasticity that decreases spine-dendrite coupling can also reduce LTP by trapping calcineurin, which dephosphorylates AMPARs. Further simulations showed that the precise timescale of neck plasticity, relative to AMPAR and enzyme diffusion and phosphorylation dynamics, critically regulates LTP. These results suggest a new mechanistic and experimentally-testable theory for how spine neck plasticity regulates synaptic plasticity.