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      Hypothalamic Somatostatin and Growth Hormone-Releasing Hormone mRNA Expression Depend upon GABA A Receptor Expression in the Developing Mouse

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          Abstract

          Gonadal steroids exert an important regulatory influence upon the biosynthetic and secretory activity of the somatostatin and growth hormone-releasing hormone (GHRH) neurons controlling the release of growth hormone. It is hypothesized that some of these effects occur in an indirect transsynaptic manner through the steroid regulation of GAGAergic inputs to these cells. Using GABA<sub>A</sub> receptor γ<sub>2</sub> subunit knockout mice (γ<sub>2</sub><sup>–/–</sup>), which exhibit marked deficiencies in GABA<sub>A</sub> receptor functioning, we have examined here whether signaling through the GABA<sub>A</sub> receptor has any role in maintaining normal levels of somatostatin and GHRH mRNA expression in vivo. In situ hybridization experiments using <sup>35</sup>S-labeled oligonucleotide probes revealed that cellular levels of somatostatin mRNA in the periventricular nucleus were significantly (p < 0.01) reduced by 16% in newborn γ<sub>2</sub><sup>–/–</sup> mice compared with wild-type litter mates (γ<sub>2</sub><sup>+/+</sup>). Somatostatin mRNA expression in the striatum was not changed. Cellular levels of GHRH mRNA expression in the arcuate nucleus were significantly (p < 0.05) reduced by 30% in γ<sub>2</sub><sup>–/–</sup> compared with γ<sub>2</sub><sup>+/+</sup> mice. These results demonstrate that deletion of the γ<sub>2</sub> subunit of the GABA<sub>A</sub> receptor reduces somatostatin and GHRH mRNA expression within the hypothalamopituitary axis and indicate that GABA exerts a tonic stimulatory influence upon both somatostatin and GHRH biosynthesis in vivo in the neonatal mouse.

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          Most cited references 6

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          Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin.

          Most fast inhibitory neurotransmission in the brain is mediated by GABAA receptors, which are mainly postsynaptic and consist of diverse alpha and beta subunits together with the gamma 2 subunit. Although the gamma 2 subunit is not necessary for receptor assembly and translocation to the cell surface, we show here that it is required for clustering of major postsynaptic GABAA receptor subtypes. Loss of GABAA receptor clusters in mice deficient in the gamma 2 subunit, and in cultured cortical neurons from these mice, is paralleled by loss of the synaptic clustering molecule gephyrin and synaptic GABAergic function. Conversely, inhibiting gephyrin expression causes loss of GABAA receptor clusters. The gamma 2 subunit and gephyrin are thus interdependent components of the same synaptic complex that is critical for postsynaptic clustering of abundant subtypes of GABAA receptors in vivo.
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            Distribution of somatostatin mRNA in the rat nervous system as visualized by a novel non-radioactive in situ hybridization histochemistry procedure

             H Kiyama,  P.C. Emson (1990)
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              Sexually Dimorphic Ontogeny of GABAergic Influences on Periventricular Somatostatin Neurons

              The biosynthesis and secretion of somatostatin (SRIH) within the hypothalamic periventricular-median eminence (PeN-ME) pathway follows a sexually differentiated developmental pattern beginning in the early neonatal period. It is generally accepted that testosterone plays a role in these processes, but the mechanisms underlying the age and sex differences are poorly understood. The present study sought to investigate the hypothesis that γ-aminobutyric acid (GABA) may play a role in determining sex differences in SRIH neuronal activity. Using an in vitro hypothalamic preparation where more than 97% of the immunoreactive SRIH is contained within the PeN-ME pathway, peptide release in response to the GABA A receptor antagonist, bicuculline, was followed through development. In the male a stimulatory response, indicative of an inhibitory GABAergic tone on SRIH secretion, was observed as early as postnatal day (P) 5. This persisted throughout juvenile development (P10, P17) and was present also in the adult male (P75), but in the peripubertal period the response to bicuculline was first lost (P25) and then reversed to an inhibition (P40), suggesting a transient switch to an apparent stimulatory GABAergic tone on SRIH release. By contrast, in the female, no bicuculline responsiveness was seen until P25 when it caused a decrease in SRIH release which persisted into adulthood. Using in situ hybridization studies we found no evidence to support the view that these age- and sex-dependent differences were due to changes in the expression of GABA A receptor α-subunits (α 1 and α 2 ) which are colocalised in the PeN SRIH neurons. Following adult gonadectomy, the bicuculline response was abolished in the male, whereas, in the female it was reversed and identical in magnitude to the response in the intact male. These results demonstrate marked sex differences in GABA A -receptor-mediated influences on SRIH release which develop soon after birth and, in the adult, depend on gonadal factors. In the male these factors activate a primarily inhibitory influence, whereas in the female they facilitate an apparently stimulatory tone of GABA on SRIH secretion via the GABA A receptor. Our findings thus support the view that GABAergic transmission may play a key role in generating sex differences in the mode of SRIH secretion from the hypothalamus which has been shown to be a major factor in determining the sexually dimorphic patterns of growth hormone secretion.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2002
                August 2002
                08 August 2002
                : 76
                : 2
                : 93-98
                Affiliations
                aLaboratory of Neuroendocrinology, The Babraham Institute, Babraham, Cambridge; bDepartment of Neuroendocrinology, Imperial College Faculty of Medicine, London, UK, and cDepartment of Biology, Pennsylvania State University, University Park, Pa., USA
                Article
                64428 Neuroendocrinology 2002;76:93–98
                10.1159/000064428
                12169770
                © 2002 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.

                Page count
                Figures: 3, References: 36, Pages: 6
                Categories
                Regulation of Growth Hormone

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