Hippocampal estradiol synthesis and its significance for hippocampal synaptic stability in male and female animals

• In females, inhibition of local estrogen synthesis results in synapse loss.
• This effect is not seen in males.
• Synapse loss in females is preceded by impairment of LTP and dephosphorylation of cofilin.

Increasing evidence points to an essential role played by neuron-derived neurosteroids, such as estrogen, on synaptic connectivity in the hippocampus. Inhibition of local estradiol synthesis results in synapse loss specifically in females, but not in males. Synapse loss in females, after inhibition of estradiol synthesis in hippocampal neurons, appears to result from impairment of long-term potentiation (LTP) and dephosphorylation of cofilin, and thereby the destabilization of postsynaptic dendritic spines. Such clear-cut effects were not seen in males. Cognitive deficits after inhibition of aromatase, the final enzyme of estrogen synthesis, have been seen in women, but not in men. Altogether, the data demonstrate distinct differences between genders in neurosteroid-induced synaptic stability.