Identification of the Prostaglandin E2 Receptors Mediating the Perinatal Organization of Male Sexual Behavior and Neuroanatomical Correlates

Abstract

The capability for an organism to reproduce not only depends on the differentiation of the reproductive organs during development but also organization of the bipotential neuroarchitecture controlling sexual behavior during a sensitive perinatal window. Prostaglandin E2 (PGE2) mediates the perinatal cellular processes organizing adult male rat sexual behavior and initiates changes to the neuroanatomy of the preoptic area (POA), a region critical for the control of this behavior. PGE2 is up-regulated in response to estradiol which is aromatized from testicular androgens and initiates a two-fold increase in the density of dendritic spines on POA neurons. PGE2 signaling is propagated through four G-protein coupled receptors, called EP1-4. In order to discover the mechanism by which PGE2 elicits its permanent effects, we will first determine which of the four receptors initiates the signal transduction cascade resulting in masculinization. Real-time PCR analysis was used to assess the developmental expression of EP1-4 mRNA in the POA. All four receptors are expressed neonatally. To identify which receptors suffice in mediating the effects of PGE2, we utilized specific agonists for each of the EP receptors and quantified: 1) measures of adult male sexual behavior, 2) levels of neonatal and adult POA spinophilin as a surrogate marker for dendritic spine formation. To identify which EP receptors are necessary for the masculinization behavior, we used a combination of antisense oligodeoxynucleotides against EP receptors followed by PGE2 administration on postnatal days 0 and 1. In female rats, neonatal treatment with antisense oligonucleotides against EP2 or EP4 but not EP1 or EP3, completely prevented the expression of adult behavior organized by PGE2 exposure. The effects of each of the EP1-4 agonists were equivalent to PGE2 treatment, suggesting that any EP receptor neonatally suffices in masculinizing adult sex behavior. Giving each agonist neonatally increased adult POA spinophilin levels. Since EP2 and EP4 are both necessary and couple to Gs proteins, we determined that PKA signaling is necessary for the organizational effects of PGE2. The body of evidence suggests that EP2 and EP4 are necessary and sufficient for PGE2-induced masculinization of sex behavior whereas EP1 and EP3 provide redundant roles.