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The Journal of Neuroscience, October 21, 2009, 29(42):13274-13282; doi:10.1523/JNEUROSCI.3603-09.2009

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

Christopher L. Wright¹ and Margaret M. McCarthy^1,2,3

¹Program in Neuroscience and Departments of ²Physiology and ³Psychiatry, University of Maryland, Baltimore, School of Medicine, Baltimore, Maryland 21201

Correspondence should be addressed to Christopher L. Wright, 655 West Baltimore Street, BRB 5-014, Baltimore, MD 21201. Email: cwrig003{at}umaryland.edu

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 G_s-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.

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Received July 25, 2009; revised Sept. 9, 2009; accepted Sept. 17, 2009.

Correspondence should be addressed to Christopher L. Wright, 655 West Baltimore Street, BRB 5-014, Baltimore, MD 21201. Email: cwrig003{at}umaryland.edu

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