Sex-dependent responsiveness of hippocampal neurons to sex neurosteroids: A role of Arc/Arg3.1.

Sex steroids, such as estradiol (E 2 ) and dihydrotestosterone (DHT), regulate hippocampal plasticity and memory in a sex-dependent manner. Because the activity-regulated cytoskeleton protein Arc/Arg3.1 is essential for long-term memory formation and synaptic plasticity, we investigated the expression of Arc/Arg3.1 with respect to its responsiveness to E 2 and DHT in male and female hippocampal neurons. For the first time, we show that, in hippocampal neurons, Arc/Arg3.1 expression is sex-dependently regulated by sex steroids. No difference in the expression between sexes was observed under control conditions. Using a quantitative real-time polymerase chain reaction, western blot analysis and quantitative immunoreactivity, upregulation of Arc/Arg3.1 protein expression was observed in specifically female hippocampal neurons after application of E 2 to the cultures. Conversely, upregulation of Arc/Arg3.1 was seen in specifically male neurons after application of DHT. A quantitative real-time PCR revealed that the sex-dependency was most pronounced on the mRNA level. Most importantly, the effects of E 2 in cultures of female animals were abolished when neuron-derived E 2 synthesis was inhibited. Our results point to a potentially important role of Arc/Arg3.1 regarding sex-dependency in sex steroid-induced synaptic plasticity in the hippocampus.