Synaptopodin is regulated by aromatase activity

Locally synthesized estradiol plays an important role in synaptic plasticity in the hippocampus. We have previously shown that in hippocampal neurons, activity of the enzyme aromatase, which converts testosterone into estradiol, is reduced via Ca2+‐dependent phosphorylation. Synaptopodin is a highly estrogen responsive protein, and it has been shown that it is an important regulator of synaptic plasticity, mediated by its close association with internal calcium stores. In this study, we show that the expression of synaptopodin is stronger in the hippocampus of female animals than in that of male animals. Phosphorylation of aromatase, using letrozole, however, down‐regulates synaptopodin immunohistochemistry in the hippocampus of both male and females. Similarly, in aromatase knock‐out mice synaptopodin expression in the hippocampus is reduced sex independently. Using primary‐dissociated hippocampal neurons, we found that evoked release of Ca2+ from internal stores down‐regulates aromatase activity, which is paralleled by reduced expression of synaptopodin. Opposite effects were achieved after inhibition of the release. Calcium‐dependent regulation of synaptopodin expression was abolished when the control of aromatase activity by the Ca2+ transients was disrupted. Our data suggest that the regulation of aromatase activity by Ca2+ transients in neurons contributes to synaptic plasticity in the hippocampus of male and female animals as an on‐site regulatory mechanism. Locally synthesized estradiol and synaptopodin, a protein closely related to internal calcium stores, play important roles in synaptic plasticity in the hippocampus. In this study, we show that Ca2+ transients from internal stores control aromatase activity, which in turn regulates synaptopdin expression. Our data introduce Ca2+‐dependent control of aromatase activity as a powerful on‐site regulatory mechanism in estrogen‐dependent synaptic plasticity in the hippocampus.