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Significance Estrogens are known to rapidly affect learning and memory, but how they do so is not well understood. Here we identify the hippocampus as a brain structure responsible for rapid estradiol-induced improvement of general discrimination learning in female mice, which coincides with a substantial increase in hippocampal dendritic spines, the postsynaptic sites of excitatory synapses. Until now, it had been assumed that estradiol-induced increases in hippocampal synapses would result in increased excitatory input into the neuron. Surprisingly, we find the opposite: increases in hippocampal spines are associated with a decrease in the excitatory glutamatergic input. This finding suggests that estradiol improves learning through inducing the formation of silent or immature synapses, which provide the substrate for storing new memories.

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements