The Function and the Expression of Forebrain GABA A Receptors Change with Hormonal State in the Adult Mouse Juan Carlos Jorge, 1 Kerry L. McIntyre, 2 Leslie P. Henderson 2,3 1 Department of Anatomy, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico 2 Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755 3 Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755 Received 3 July 2001; accepted 6 September 2001 ABSTRACT: Neurotransmission mediated by gamma-aminobutyric acid type A (GABA A ) receptors in the mammalian medial preoptic area (mPOA) plays a pivotal role in the expression of hormone-sensitive be- haviors. Hand in hand with GABAergic control of re- production, hormone treatments that activate gonadal steroid signaling pathways in gonadectomized rats are known to regulate the expression of specific GABA A receptor subunit mRNAs. While the effects of exogenous hormone treatments have been well documented, little information is available as to how GABA A receptor- mediated transmission in the mPOA is altered by endog- enous changes in hormonal state in gonadally-intact adult animals or if those changes can be ascribed to hormone-dependent changes in receptor subunit compo- sition. In the present study, we found that both the peak amplitudes of GABA A receptor-mediated synaptic cur- rents in the mPOA, as well as the ability of the endog- enous neurosteroids to modulate those currents, varied as a function of the estrous cycle. Moreover, we found that the degree of neurosteroid modulation was also significantly different between wild-type and the andro- gen-insensitive testicular feminization (Tfm) mutant male mice. Semiquantitative RT-PCR analysis per- formed to assess levels of GABA A receptor subunit mRNAs indicated that levels of specific subunits varied over the course of the estrous cycle and between wild- type and Tfm male mice. The variations in GABA A receptor expression and function in the mPOA that are associated with differences in gonadal steroid signaling may contribute to the dynamic nature of GABAergic control of neuroendocrine pathways. © 2002 John Wiley & Sons, Inc. J Neurobiol 50: 137–149, 2002; DOI 10.1002/neu.10021 Keywords: GABA A receptor; estrous cycle; medial pre- optic area; Tfm; neurosteroid INTRODUCTION Neurotransmission mediated by GABA A receptors in the medial preoptic area (mPOA) plays a critical role in the control of reproduction. For example, GABAer- gic transmission in the mPOA regulates the activity of forebrain gonadotropin-releasing hormone (GnRH) neurons and the pulsatile secretion of gonadotropins that is required for the onset of puberty and regular estrous cyclicity (Herbison et al., 1991; for review, Kordon et al., 1994; Ojeda and Urbanski, 1994). In addition, GABAergic transmission in the mPOA modulates the expression of both male (for review, Fernandez-Guasti et al., 1986) and female (for review, McCarthy, 1995) sexual behaviors. While GABAer- gic transmission regulates steroid-sensitive neural cir- cuits, gonadal steroids, in turn, have significant effects Correspondence to: L. P. Henderson (leslie.henderson@ dartmouth.edu). Contract grant sponsor: NIH; contract grant numbers: NS28668 and DA1416 (L.P.H.) and P20RR15565 (J.C.J.). Contract grant sponsor: NSF; contract grant number: DBI- 9707826 (J.C.J). © 2002 John Wiley & Sons, Inc. 137