Sex‐dependency of oestrogen‐induced structural synaptic plasticity: Inhibition of aromatase versus application of estradiol in rodents

Sex‐dependent differences in learning and memory formation in humans have been frequently shown. The mechanisms underlying the formation and retention of memories are assumed to involve synaptic plasticity in the hippocampus. Estradiol was shown to effect synaptic plasticity in the hippocampus of rodents. The effects after exogenous application of estradiol to animals frequently produce inconsistent results, in particular, if sex is not considered in the studies. Recently we provided evidence that locally synthesized estradiol plays an essential role on synaptic connectivity in the hippocampus of females but not of male mice. In females, inhibition of local estradiol synthesis leads to synapse loss, which results from impairment of long‐term potentiation and dephosphorylation of cofilin, and thereby the destabilization of postsynaptic dendritic spines. This sex‐dependency was also seen in the classical aromatase knock‐out mouse. Intriguingly, no differences between sexes have been found in a conditional forebrain‐specific aromatase knock‐out mouse. Altogether, the findings underscore the necessity of including ‘Sex as a Biological Variable’ in studies of sex steroid‐induced synaptic plasticity. From the numerous studies in the field of oestrogen‐induced synaptic plasticity during the passed 30 years, it emerges that brain‐derived estradiol effects synaptic plasticity in a paracrine manner in the female but not in the male hippocampus. This sex‐dependency was also seen in the classical aromatase knock‐out mouse. Estradiol synthesis in the female hippocampus and as a consequence LTP and synaptic density are controlled by GnRH from the hypothalamus, which may explain oestrous cycle dependency of synaptic plasticity.