Prostaglandin E2-Induced Masculinization of Brain and Behavior Requires Protein Kinase A, AMPA/Kainate, and Metabotropic Glutamate Receptor Signaling

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Abstract
Prostaglandin E2(PGE2) mediates the masculinization of adult sex behavior in rats in response to the surge in serum testosterone at approximately birth. Measures of behavioral masculinization correlate with a twofold increase in spinophilin protein and the density of dendritic spines in the medial preoptic area (POA). Of the four receptors for PGE2, EP2and EP4are required for the masculinization of behavior by PGE2. EP2and EP4couple to Gs-proteins, activating protein kinase A (PKA). By using H89 (N-[2-(p-bromo-cinnamylamino)-ethyl]-5-isoquinoline-sulfon-amide 2HCl) and Ht31, disruptors of PKA signaling, we have determined that PKA signaling is required for the masculinization of behavior by PGE2. Glutamatergic signaling often mediates PGE2signaling; therefore, we tested whether inhibition of AMPA/kainate and metabotropic glutamate receptor (mGluR) signaling prevents PGE2-induced behavioral masculinization and whether activation of glutamate receptors mimics PGE2. Females treated neonatally with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) plus LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] combined (AMPA/kainate and mGluR inhibitors, respectively) before PGE2did not exhibit as many mounts or intromission-like behaviors or initiate these behaviors as quickly as animals treated with PGE2alone. Animals neonatally treated with kainate, (±)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) (type I mGluR agonist), or the two combined mounted as frequently and initiated mounting behavior as quickly as those given PGE2. Ht31 does not prevent the masculinization of behavior by ACPD plus kainate cotreatment; rather, the coadministration of NBQX plus LY341495 prevents the forskolin-induced formation of POA dendritic spine-like processes. We conclude that PKA, AMPA/kainate, and metabotropic glutamate receptor signaling are necessary for the effects of PGE2, that each receptor individually suffices to organize behavior, and that PKA is upstream of the glutamate receptors.