Presynaptic occlusion of long lasting NMDAR-dependent potentiation in Synaptophysin family knockouts

Synaptophysin family proteins are abundant components of synaptic vesicle membranes. Exocytosis is enhanced in knockouts, suggesting that family members are negative regulators of neurotransmission. Here we confirm previous reports of severe deficits in long-term potentiation (LTP) at Schaffer collateral synapses under experimental conditions that are standard for ex vivo experiments. However, LTP could be fully rescued by lowering extracellular Ca ²⁺ enough to decrease baseline synaptic vesicle exocytosis to wildtype levels. Conversely, the deficit in LTP could be recapitulated at wildtype synapses by raising Ca ²⁺ enough to increase baseline to knockout levels. Moreover, LTP induction was intact at both knockout and wildtype synapses under conditions where expression was blocked. The results indicate that the longest-lasting components of LTP expression are limited at a late stage in synaptic vesicle exocytosis from presynaptic terminals, and provide a straightforward new experimental strategy for dissecting apart mechanisms underlying induction and expression.