Fig. 4.

Estrogen-induced “two-step wiring plasticity” in cortical neurons. This form of “wiring” plasticity can be divided into three distinct phases. Phase 1: treatment with 17 β-estradiol induces the formation of novel spines, which form connections with pre-synaptic partners within 30 minutes. Concurrently GluA1-containing AMPA receptors are removed from existing spines, and GluN1-containing NMDA receptors are trafficked into nascent spines. Overall, this results in an increased number of connections between cells and a reduction in AMPA receptor transmission. Phase 2A: effect on dendritic spines and glutamate receptors is transient: 60 minutes after treatment, estradiol-induced spines are preferentially eliminated and GluA1-containing AMPA receptors and GluN1-containing NMDA receptors return to control levels. Therefore, the number of connections returns to control levels, and AMPA receptor-transmission returns to normal. Or, Phase 2B: addition of a second synaptic activity-like stimulus results in the stabilization of estradiol-induced spines and a trafficking of GluA1-containing AMPA receptors back into existing and nascent synapses as observed immediately after the completion of treatment or 24 hours post-treatment. This combined treatment may lead to long-lasting (24 hour) increase in connectivity and increase synaptic communication.