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      Lack of Functional GABA B Receptors Alters Kiss1 , Gnrh1 and Gad1 mRNA Expression in the Medial Basal Hypothalamus at Postnatal Day 4

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          Abstract

          Background/Aims: Adult mice lacking functional GABA<sub>B</sub> receptors (GABA<sub>B1</sub>KO) show altered Gnrh1 and Gad1 expressions in the preoptic area-anterior hypothalamus (POA-AH) and females display disruption of cyclicity and fertility. Here we addressed whether sexual differentiation of the brain and the proper wiring of the GnRH and kisspeptin systems were already disturbed in postnatal day 4 (PND4) GABA<sub>B1</sub>KO mice. Methods: PND4 wild-type (WT) and GABA<sub>B1</sub>KO mice of both sexes were sacrificed; tissues were collected to determine mRNA expression (qPCR), amino acids (HPLC), and hormones (RIA and/or IHC). Results: GnRH neuron number (IHC) did not differ among groups in olfactory bulbs or OVLT-POA. Gnrh1 mRNA (qPCR) in POA-AH was similar among groups. Gnrh1 mRNA in medial basal hypothalamus (MBH) was similar in WTs but was increased in GABA<sub>B1</sub>KO females compared to GABA<sub>B1</sub>KO males. Hypothalamic GnRH (RIA) was sexually different in WTs (males > females), but this sex difference was lost in GABA<sub>B1</sub>KOs; the same pattern was observed when analyzing only the MBH, but not in the POA-AH. Arcuate nucleus Kiss1 mRNA (micropunch-qPCR) was higher in WT females than in WT males and GABA<sub>B1</sub>KO females. Gad1 mRNA in MBH was increased in GABA<sub>B1</sub>KO females compared to GABA<sub>B1</sub>KO males. Serum LH and gonadal estradiol content were also increased in GABA<sub>B1</sub>KOs. Conclusion: We demonstrate that GABA<sub>B</sub>Rs participate in the sexual differentiation of the ARC/MBH, because sex differences in several reproductive genes, such as Gad1, Kiss1 and Gnrh1, are critically disturbed in GABA<sub>B1</sub>KO mice at PND4, probably altering the organization and development of neural circuits governing the reproductive axis.

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          GABA(B)-receptor subtypes assemble into functional heteromeric complexes.

          B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channels and adenylyl cyclase. Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA(B) receptors, so it is expected that GABA(B)-receptor (GABA(B)R) subtypes exist. Two GABA(B)-receptor splice variants have been cloned (GABA(B)R1a and GABA(B)R1b), but native GABA(B) receptors and recombinant receptors showed unexplained differences in agonist-binding potencies. Moreover, the activation of presumed effector ion channels in heterologous cells expressing the recombinant receptors proved difficult. Here we describe a new GABA(B) receptor subtype, GABA(B)R2, which does not bind available GABA(B) antagonists with measurable potency. GABA(B)R1a, GABA(B)R1b and GABA(B)R2 alone do not activate Kir3-type potassium channels efficiently, but co-expression of these receptors yields a robust coupling to activation of Kir3 channels. We provide evidence for the assembly of heteromeric GABA(B) receptors in vivo and show that GABA(B)R2 and GABA(B)R1a/b proteins immunoprecipitate and localize together at dendritic spines. The heteromeric receptor complexes exhibit a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors and probably represent the predominant native GABA(B) receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.
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            Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus.

            The gonadotrophin-releasing hormone (GnRH) neurones represent the final output neurones of a complex neuronal network that controls fertility. It is now appreciated that GABAergic neurones within this network provide an important regulatory influence on GnRH neurones. However, the consequences of direct GABA(A) receptor activation on adult GnRH neurones have been controversial for nearly a decade now, with both hyperpolarising and depolarising effects being reported. This review provides: (i) an overview of GABA(A) receptor function and its investigation using electrophysiological approaches and (ii) re-examines the past and present results relating to GABAergic regulation of the GnRH neurone, with a focus on mouse brain slice data. Although it remains difficult to reconcile the results of the early studies, there is a growing consensus that GABA can act through the GABA(A) receptor to exert both depolarising and hyperpolarising effects on GnRH neurones. The most recent studies examining the effects of endogenous GABA release on GnRH neurones indicate that the predominant action is that of excitation. However, we are still far from a complete understanding of the effects of GABA(A) receptor activation upon GnRH neurones. We argue that this will require not only a better understanding of chloride ion homeostasis in individual GnRH neurones, and within subcellular compartments of the GnRH neurone, but also a more integrative view of how multiple neurotransmitters, neuromodulators and intrinsic conductances act together to regulate the activity of these important cells. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.
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              Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function.

              GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over-expression of candidate genes in mouse models. Importantly, a number of these factors may not only play a role in normal physiology of the hypothalamic-pituitary-gonadal axis but also be mis-expressed to cause human disorders of GnRH deficiency, presenting as a failure to undergo normal pubertal development. This review outlines the current cadre of candidates thought to modulate GnRH neuronal migration. The further elucidation and characterization of these factors that impact GnRH neuron development may shed new light on human reproductive disorders and provide potential targets to develop new pro-fertility or contraceptive agents. Published by Elsevier Inc.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2013
                December 2013
                06 November 2013
                : 98
                : 3
                : 212-223
                Affiliations
                aLaboratorio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), bFacultad de Farmacia y Bioquímica and cFacultad de Medicina, Universidad de Buenos Aires, Buenos Aires, and dIIB-INTECH, CONICET-UNSAM, Chascomús, Argentina; eDepartment of Reproductive Medicine, University of California, San Diego, Calif., USA; fDepartment of Biomedicine, University of Basel, Basel, Switzerland
                Author notes
                *Victoria Lux-Lantos, PhD, V. de Obligado 2490 (C1428ADN), Buenos Aires (Argentina), E-Mail vlux@ibyme.conicet.gov.ar
                Article
                355631 PMC3915412 Neuroendocrinology 2013;98:212-223
                10.1159/000355631
                PMC3915412
                24080944
                1bce0716-6444-413d-adb4-13f7f62ef124
                © 2013 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 26 March 2013
                : 10 September 2013
                Page count
                Figures: 6, Tables: 1, Pages: 12
                Categories
                Original Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                GABA,GABAB receptors,Sex steroids,Gonadotropins, Kiss1 ,GnRH

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