A synapse-specific refractory period for plasticity at individual dendritic spines

How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity become resistant to further plasticity, a type of metaplasticity often referred to as saturation. Here, we probe the local dendritic mechanisms that limit plasticity at recently potentiated synapses. We show that recently potentiated individual synapses exhibit a synapse-specific refractory period for further potentiation. We further found that the refractory period is associated with reduced postsynaptic CaMKII signaling; however, stronger synaptic activation only partially restored the ability for further plasticity. Importantly, the refractory period is released after one hour, a timing that coincides with the enrichment of several postsynaptic proteins to pre-plasticity levels. Notably, increasing the level of the postsynaptic scaffolding protein, PSD95, but not of PSD93, overcomes the refractory period. Our results support a model in which potentiation at a single synapse is sufficient to initiate a synapse-specific refractory period that persists until key postsynaptic proteins regain their steady-state synaptic levels. Significance StatementA refractory period in which newly modified synaptic connections are unable to undergo further plasticity is a proposed mechanism through which newly formed memories can be preserved at the synaptic level while brain plasticity is ongoing. Here, we provide new insights into the spatiotemporal signaling mechanisms that regulate the establishment and maintenance of a refractory period for plasticity at individual excitatory synapses in the hippocampus, a region of the brain vital for learning and memory. Our results have implications in the identification of molecular targets that could serve to improve learning outcomes associated with disease.