Sex differences in GABA turnover and glutamic acid decarboxylase (GAD65 and GAD67) mRNA in the rat hypothalamus

Searles, Robin V.; Yoo, Mi-Jeong; He, Ju‐Ren; Shen, Wei-Bin; Selmanoff, Michael

doi:10.1016/s0006-8993(00)02648-2

Cited by 42 publications

(29 citation statements)

References 66 publications

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“…In addition, GABA B1 KO females showed a significant increase in GABA and glutamate levels with regard to their WT controls. Moreover, GAD-67 mRNA also shows a clear sexually dimorphic expression in the POA-AH of WT mice, as previously described in other brain areas (84). This sex difference is also lost in GABA B1 KO animals; in fact, a sexual inversion in GAD-67 mRNA expression is observed in this genotype, identical to the one observed for GnRH mRNA in the POA-AH.…”

Section: Neurotransmitter Content and Gad-67 Expressionsupporting

confidence: 82%

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Lack of functional GABA_B receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Catalano

Giorgio

Bonaventura

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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GABA, the main inhibitory neurotransmitter, acts through GABAA/C and GABAB receptors (GABABRs); it is critical for gonadotropin regulation. We studied whether the lack of functional GABABRs in GABAB1 knockout (GABAB1KO) mice affected the gonadotropin axis physiology. Adult male and female GABAB1KO and wild-type (WT) mice were killed to collect blood and tissue samples. Gonadotropin-releasing hormone (GnRH) content in whole hypothalami (HT), olfactory bulbs (OB), and frontoparietal cortexes (CT) were determined (RIA). GnRH expression by quantitative real-time PCR (qRT-PCR) was evaluated in preoptic area-anterior hypothalamus (POA-AH), medial basal-posterior hypothalamus (MBH-PH), OB, and CT. Pulsatile GnRH secretion from hypothalamic explants was measured by RIA. GABA, glutamate, and taurine contents in HT and CT were determined by HPLC. Glutamic acid decarboxylase-67 (GAD-67) mRNA was measured by qRT-PCR in POA-AH, MBH-PH, and CT. Gonadotropin content, serum levels, and secretion from adenohypophyseal cell cultures (ACC) were measured by RIA. GnRH mRNA expression was increased in POA-AH of WT males compared with females; this pattern of expression was inversed in GABAB1KO mice. MBH-PH, OB, and CT did not follow this pattern. In GABAB1KO females, GnRH pulse frequency was increased and GABA and glutamate contents were augmented. POA-AH GAD-67 mRNA showed the same expression pattern as GnRH mRNA in this area. Gonadotropin pituitary contents and serum levels showed no differences between genotypes. Increased basal LH secretion and decreased GnRH-stimulated gonadotropin response were observed in GABAB1KO female ACCs. These results support the hypothesis that the absence of functional GABABRs alters GnRH physiology and critically affects sexual dimorphic expression of GnRH and GAD-67 in POA-AH.

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Section: Neurotransmitter Content and Gad-67 Expressionsupporting

confidence: 82%

“…In adult WT mice, GABA, glutamate, and taurine titers show clear sexually dimorphic levels in the hypothalamus, with male levels higher than those of females, as previously shown for GABA in rats (38,84). Importantly, this sex difference is lost in GABA B1 KO mice for both GABA and glutamate.…”

Section: Neurotransmitter Content and Gad-67 Expressionsupporting

confidence: 71%

Lack of functional GABA_B receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Catalano

Giorgio

Bonaventura

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…For example, it appears that GABA is responsible in part for the inhibition of luteinizing hormone-releasing hormone release before the onset of puberty in female rhesus monkeys, 99 and sex differences in GABA turnover and GAD 65 and GAD 67 transcript levels have been observed in the rat hypothalamus. 100 Finally, in the olfactory bulb of adult rats, a region of high synaptic plasticity, estrogen modulates in a cyclic manner, a truncated version of the 'embryonic' isoform GAD25. 101 It is also likely that the effects of alterations in GABA signaling on cortical excitability differentially impact on cortical function in the males and females because of other genetic and environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

et al. 2007

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Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD 67 ), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5 0 flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5 0 untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.

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“…Investigations have further demonstrated that GABA acts principally through GABA A receptors located within the vicinity of the GnRH cell bodies to modulate LH secretion [17, 18, 19, 20, 24]and both electron-microscopic [25]and GABA A receptor subunit colocalization [26, 27]studies indicate the presence of GABA A receptors on GnRH neurons in the female rat. Although it is not known if sex differences exist in the direct GABAergic regulation of the GnRH neurons, sex differences in GABA turnover have been reported in the rat preoptic area [28, 29]and whole brain GABA manipulation exerts sexually dimorphic effects of on LH secretion [30]. …”

Section: Introductionmentioning

confidence: 99%

Profiling γ-Aminobutyric Acid (GABA<sub>A</sub>) Receptor Subunit mRNA Expression in Postnatal Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mouse with Single Cell RT-PCR

Pape¹,

Skynner²,

Sim³

et al. 2001

Neuroendocrinology

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The present investigation has examined which subunits of the GABA_A receptor are expressed by gonadotropin-releasing hormone (GnRH) neurons in the juvenile and adult male mouse. Cells of defined morphology, located in the medial septum (MS) and rostral preoptic area (POA), were patch-clamped in the acute brain slice preparation and their cell contents extracted. A reverse transcriptase polymerase chain reaction (RT-PCR) procedure using nested primers was used to establish individual GnRH mRNA-expressing cells which were then evaluated for eleven GABA_A receptor (α1–5, β1–3, γ1–3) subunit transcripts. Single and multiple GABA_A receptor subunit mRNAs were detected in approximately 70% of all GnRH neurons. A range of different subunit mRNAs (α1, α2, α5, β1, β2, β3, γ2) were found in juvenile GnRH neurons, with the α1γ2 and α5γ2 combinations encountered most frequently within individual cells. The expression profile in adult GnRH neurons was more extensive than that detected in juveniles with α1, α2, α3, α5, β1, β2, β3, γ1 and γ2 subunits all being detected. The major difference in subunit profile between GnRH neurons located in the MS and POA involved the β subunits. The principal postnatal developmental change was one of increasing overall subunit heterogeneity in maturing POA GnRH neurons. The profile of GABA_A receptor subunit mRNAs detected in male GnRH neurons was quite different to that reported by us for female GnRH neurons in the mouse using the same RT-PCR approach. Together, these findings indicate that postnatal GnRH neurons are likely to express a range of GABA_A receptor subunit mRNAs in a sexually dimorphic and developmentally-regulated manner.

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Sex differences in GABA turnover and glutamic acid decarboxylase (GAD65 and GAD67) mRNA in the rat hypothalamus

Cited by 42 publications

References 66 publications

Lack of functional GABA_B receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Lack of functional GABA_B receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

Profiling γ-Aminobutyric Acid (GABA<sub>A</sub>) Receptor Subunit mRNA Expression in Postnatal Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mouse with Single Cell RT-PCR

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Sex differences in GABA turnover and glutamic acid decarboxylase (GAD65 and GAD67) mRNA in the rat hypothalamus

Cited by 42 publications

References 66 publications

Lack of functional GABAB receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Lack of functional GABAB receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

Profiling γ-Aminobutyric Acid (GABA<sub>A</sub>) Receptor Subunit mRNA Expression in Postnatal Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mouse with Single Cell RT-PCR

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Lack of functional GABA_B receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain

Lack of functional GABA_B receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain