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

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, EP2 and EP4 are required for the masculinization of behavior by PGE2. EP2 and EP4 couple 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 PGE2 signaling; 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 PGE2 did not exhibit as many mounts or intromission-like behaviors or initiate these behaviors as quickly as animals treated with PGE2 alone. 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.

[1]  R. Anwyl.  Metabotropic glutamate receptor-dependent long-term potentiation , 2009, Neuropharmacology.

[2]  M. Bennett,et al.  Developmental switch in requirement for PKA RIIβ in NMDA-receptor-dependent synaptic plasticity at Schaffer collateral to CA1 pyramidal cell synapses , 2009, Neuropharmacology.

[3]  R. Breyer,et al.  Altered hippocampal long‐term synaptic plasticity in mice deficient in the PGE2 EP2 receptor , 2009, Journal of neurochemistry.

[4]  M. McCarthy,et al.  Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates , 2008, Developmental neurobiology.

[5]  K. Tominaga-Yoshino,et al.  Repetitive induction of late‐phase LTP produces long‐lasting synaptic enhancement accompanied by synaptogenesis in cultured hippocampal slices , 2008, Hippocampus.

[6]  L. Coolen,et al.  Mating activates NMDA receptors in the medial preoptic area of male rats. , 2007, Behavioral neuroscience.

[7]  M. McCarthy,et al.  Exploration of prostanoid receptor subtype regulating estradiol and prostaglandin E2 induction of spinophilin in developing preoptic area neurons , 2007, Neuroscience.

[8]  S. Narumiya,et al.  Prostaglandin E Receptors* , 2007, Journal of Biological Chemistry.

[9]  J. Mong,et al.  Glutamate AMPA/kainate receptors, not GABAA receptors, mediate estradiol‐induced sex differences in the hypothalamus , 2007, Developmental neurobiology.

[10]  E. Hull,et al.  Preoptic Glutamate Facilitates Male Sexual Behavior , 2006, The Journal of Neuroscience.

[11]  K. E. Smith,et al.  Regulation of neuronal PKA signaling through AKAP targeting dynamics. , 2006, European journal of cell biology.

[12]  John D. Scott,et al.  Association of an A-kinase-anchoring protein signaling scaffold with cadherin adhesion molecules in neurons and epithelial cells. , 2005, Molecular biology of the cell.

[13]  M. Bear,et al.  Role for A Kinase-anchoring Proteins (AKAPS) in Glutamate Receptor Trafficking and Long Term Synaptic Depression* , 2005, Journal of Biological Chemistry.

[14]  Kentaro Abe,et al.  Synaptic contact dynamics controlled by cadherin and catenins. , 2005, Trends in cell biology.

[15]  R. Malenka,et al.  Multiple functions for the cadherin/catenin complex during neuronal development , 2004, Neuropharmacology.

[16]  Cynthia L. Jordan,et al.  Sexual differentiation of the vertebrate nervous system , 2004, Nature Neuroscience.

[17]  M. Bond,et al.  A-kinase anchoring protein targeting of protein kinase A in the heart. , 2004, Journal of molecular and cellular cardiology.

[18]  M. McCarthy,et al.  Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior , 2004, Nature Neuroscience.

[19]  J. Regan.  EP2 and EP4 prostanoid receptor signaling. , 2003, Life sciences.

[20]  John D. Scott,et al.  AKAP mediated signal transduction. , 2003, Annual review of pharmacology and toxicology.

[21]  E. Hull,et al.  An NMDA antagonist impairs copulation and the experience-induced enhancement of male sexual behavior in the rat. , 2003, Behavioral neuroscience.

[22]  M. McCarthy,et al.  A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E2 , 2002, The Journal of Neuroscience.

[23]  Tullio Pozzan,et al.  Prostaglandins stimulate calcium-dependent glutamate release in astrocytes , 1998, Nature.

[24]  D. Lubahn,et al.  Masculine Sexual Behavior Is Disrupted in Male and Female Mice Lacking a Functional Estrogen Receptor α Gene , 1997, Hormones and Behavior.

[25]  J. Scott,et al.  Mutational Analysis of the A-Kinase Anchoring Protein (AKAP)-binding Site on RII , 1996, The Journal of Biological Chemistry.

[26]  Rubin Cs.  A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP. , 1994 .

[27]  J. Regan,et al.  Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype. , 1994, Molecular pharmacology.

[28]  E. Hull,et al.  A D1 agonist in the MPOA facilitates copulation in male rats , 1994, Pharmacology Biochemistry and Behavior.

[29]  Y. Sugimoto,et al.  Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 subtype. , 1993, The Journal of biological chemistry.

[30]  V. Hillegaart,et al.  Stimulation of 5-HT1A and 5-HT1B receptors in brain regions and its effects on male rat sexual behaviour. , 1992, European journal of pharmacology.

[31]  B. McEwen,et al.  Aromatization: Important for sexual differentiation of the neonatal rat brain , 1977, Hormones and Behavior.

[32]  B D Sachs,et al.  Ejaculatory pattern in female rats without androgen treatment , 1975, Science.

[33]  P. Södersten,et al.  Female lordosis behavior in estrogen-primed male rats treated with p-chlorophenylalanine or ?-methyl-p-tyrosine , 1972 .

[34]  L. Heimer,et al.  Mating Behaviour of Male Rats after Lesions in the Preoptic Area , 1964, Nature.

[35]  W. C. Young,et al.  Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. , 1959, Endocrinology.

[36]  H. Olivecrona,et al.  Evidence for the participation of the preoptic area in male mating behaviour , 1954, Experientia.

[37]  C. Wright.  Identification of the prostaglandin E2 receptors mediating the perinatal organization of male sexual behavior and neuroanatomical correlates , 2009 .

[38]  Margaret M McCarthy,et al.  Estradiol and the developing brain. , 2008, Physiological reviews.

[39]  Alison L. Barth,et al.  A developmental switch in the signaling cascades for LTP induction , 2003, Nature Neuroscience.

[40]  L. Raymond,et al.  Regulation of ligand-gated ion channels by protein phosphorylation. , 1999, Advances in second messenger and phosphoprotein research.

[41]  C. Rubin,et al.  A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP. , 1994, Biochimica et biophysica acta.

[42]  P. Södersten.  Sexual differentiation: do males differ from females in behavioral sensitivity to gonadal hormones? , 1984, Progress in brain research.

[43]  I. J. Davies,et al.  The formation and metabolism of estrogens in brain tissues. , 1975, Advances in the biosciences.

[44]  L. Wolin,et al.  The formation of estrogens by central neuroendocrine tissues. , 1975, Recent progress in hormone research.

[45]  P. Södersten,et al.  Female lordosis behavior in estrogen-primed male rats treated with para-chlorophenylalanine or alpha-methyl-para-tyrosine. , 1972, Hormones and Behavior.