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The Journal of Neuroscience, August 6, 2008, 28(32):8003-8013; doi:10.1523/JNEUROSCI.1225-08.2008
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Behavioral/Systems/Cognitive
Excitatory Effects of the Puberty-Initiating Peptide Kisspeptin and Group I Metabotropic Glutamate Receptor Agonists Differentiate Two Distinct Subpopulations of Gonadotropin-Releasing Hormone Neurons
Iryna Dumalska,1
Min Wu,1
Elena Morozova,1
Rongjian Liu,1
Anthony van den Pol,2 and
Meenakshi Alreja1,3
Departments of 1Psychiatry, 2Neurosurgery, and 3Neurobiology, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut 06508
Correspondence should be addressed to Meenakshi Alreja, Department of Psychiatry, CMHC 335A, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508. Email: Meenakshi.Alreja{at}yale.edu
Activation of the G-protein-coupled receptor GPR54 by kisspeptins during normal puberty promotes the central release of gonadotropin-releasing hormone (GnRH) that, in turn, leads to reproductive maturation. In humans and mice, a loss of function mutations of GPR54 prevents the onset of puberty and leads to hypogonadotropic hypogonadism and infertility. Using electrophysiological, morphological, molecular, and retrograde-labeling techniques in brain slices prepared from vGluT2-GFP and GnRH-GFP mice, we demonstrate the existence of two physiologically distinct subpopulations of GnRH neurons. The first subpopulation is comprised of septal GnRH neurons that colocalize vesicular glutamate transporter 2 and green fluorescent protein and is insensitive to metabotropic glutamate receptor agonists, but is exquisitely sensitive to kisspeptin which closes potassium channels to dramatically initiate a long-lasting activation in neurons from prepubertal and postpubertal mice of both sexes. A second subpopulation is insensitive to kisspeptin but is uniquely activated by group I metabotropic glutamate receptor agonists. These two physiologically distinct classes of GnRH cells may subserve different functions in the central control of reproduction and fertility.
Key words: GPR54; LH; FSH; brain slice; gonadotropins; hypogonadism
Received July 23, 2007;
revised July 1, 2008;
accepted July 2, 2008.
Correspondence should be addressed to Meenakshi Alreja, Department of Psychiatry, CMHC 335A, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508. Email: Meenakshi.Alreja{at}yale.edu
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