Regulation of synaptic plasticity in amygdala mediated by neuron-synthetized sexual hormones (sex neurosteroids)

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Neurons are capable of synthesizing sex steroid hormones which are released as neurosteroids and influence neuronal connectivity. The functions of these sex neurosteroids have been intensely studied in hippocampus, where endogenously synthesized 17beta-estradiol (E2) and dihydrotestosterone (DHT) have been shown to regulate the stability and properties of excitatory synapses in a sex-specific manner. We recently showed that similar mechanisms are also effective in amygdala. We found in basolateral amygdala (BLA) a robust expression of the E2-synthesizing enzyme aromatase (AROM) and showed that inhibition of AROM results sex-specifically in altered spine synapse density and LTP. In addition, robust AROM expression was found in the lateral part of the central amygdala (CeAl), which together with BLA is pivotal for the fear response. This raises the questions what mechanisms underlie the sex-specific regulation of synaptic plasticity by E2, and whether they influence fear behavior sex-dependently. In the present proposal, we suggest experiments aimed at comprehensively addressing these questions. As 5alpha-reductase type 2 (5alpha-R2), the enzyme that generates DHT, is also strongly expressed both in BLA and CeAl, we further include studies addressing the function of DHT into our proposal. Experimental models include: a) Analysis of AROM- and androgen receptor (AR)-deficient mice, and b) intraventricular infusion of inhibitors of AROM and 5alpha-R2 (letrozole and finasteride, respectively) into adult gonadectomized rats. Animals are subsequently analyzed for altered synaptic plasticity in BLA and CeAl, and for altered fear-related behavior. c) Organotypic cultures including amygdala, which will be used to identify the molecular mechanisms of sex neurosteroid signaling in BLA. In addition, we will d) determine expression profiles of neurons which express AROM, 5alpha-R2, estrogen and/or androgen receptors in BLA and CeAl. We believe that these studies will provide valuable information that may help to better understand certain sex differences in mood disorders as well as side effects of the inhibitors, which are frequently used for cancer therapy (breast and prostate cancer, respectively).