Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females

Qiu, Jian; Rivera, Heidi M.; Bosch, Martha A.; Padilla, Stéphanie L.; Stincic, Todd L.; Palmiter, Richard D.; Kelly, Martin J.; Rønnekleiv, Oline K.

doi:10.7554/elife.35656

Cited by 89 publications

(149 citation statements)

References 87 publications

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“…While the effects of E2 and ghrelin in ARC KNDy neurons have become more defined, it is critical to keep in mind that KNDy neurons are one node of a large circuit within the ARC. KNDy neurons not only project locally to POMC and NPY neurons but also to preoptic GnRH and kisspeptin neurons of the AVPV, playing an important role in puberty and ovarian functions [37,47]. KNDy neurons activate POMC neurons via kisspeptin and glutamate release and inhibit NPY neurons directly via glutamate and indirectly through kisspeptin [16,37].…”

Section: Discussionmentioning

confidence: 99%

“…KNDy neurons not only project locally to POMC and NPY neurons but also to preoptic GnRH and kisspeptin neurons of the AVPV, playing an important role in puberty and ovarian functions [37,47]. KNDy neurons activate POMC neurons via kisspeptin and glutamate release and inhibit NPY neurons directly via glutamate and indirectly through kisspeptin [16,37]. As all 3 neurons modulate the excitability of the other 2 neuronal populations and respond differently to peripheral peptide hormones, any modulation of one neuronal population by a hormone will have disparate effects on the other 2 popu-…”

Section: Discussionmentioning

confidence: 99%

“…During states of elevated E2 (proestrus or ovariectomy with E2 replacement), GHSR expression is increased in KNDy neurons, augmenting KNDy sensitivity to ghrelin. These transcriptional effects produce KNDy neurons more sensitive to states of elevated ghrelin (fasting, caloric restriction), increasing KNDy neuronal output, kisspeptin or glutamate release onto ARC POMC and NPY neurons [37]. POMC activation would increase the release of β-endorphin on GnRH neurons to suppress LH pulsatility [23].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, as ghrelin administration suppresses LH pulsatility through β-endorphin produced by POMC neurons in fed female rats [18,29], ghrelin activation of KNDy neurons may be involved, as GHSR is not highly expressed in POMC neurons [23]. Indeed, KNDy neurons can excite POMC neurons via glutamate during states of elevated E2 [37], which may lead to greater β-endorphin release onto GnRH terminals, inhibiting LH pulsatility. Hence, during states of elevated ghrelin (fasting, food scarcity, etc.…”

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confidence: 99%

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17β-Estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-Current in Female Mice

Conde¹,

Roepke²

2019

Neuroendocrinology

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Obesity and anorexia result in dysregulation of the hypothalamic-pituitary-gonadal axis, negatively impacting reproduction. Ghrelin, secreted from the stomach, potentially mediates negative energy states and neuroendocrine control of reproduction by acting through the growth hormone secretagogue receptor (GHSR). GHSR is expressed in hypothalamic arcuate (ARC) Kisspeptin/Neurokinin B (Tac2)/Dynorphin (KNDy) neurons. Ghrelin is known to inhibit the M-current produced by KCNQ channels in other ARC neurons. In addition, we have shown 17β-estradiol (E2) increases Ghsr expression in KNDy neurons 6-fold and increases the M-current in NPY neurons. We hypothesize that E2 increases GHSR expression in KNDy neurons to increase ghrelin sensitivity during negative energy states. Furthermore, we suspect ghrelin targets the M-current in KNDy neurons to control reproduction and energy homeostasis. We utilized ovariectomized Tac2-EGFP adult female mice, pretreated with estradiol ben-zoate (EB) or oil vehicle and performed whole-cell-patchclamp recordings to elicit the M-current in KNDy neurons using standard activation protocols in voltage-clamp. Using the selective KCNQ channel blocker XE-991 (40 µM) to target the M-current, oil-and EB-treated mice showed a decrease in the maximum peak current by 75.7 ± 13.8 pA (n = 10) and 68.0 ± 14.7 pA (n = 11), respectively. To determine the actions of ghrelin on the M-current, ghrelin was perfused (100 nM) in oil-and EB-treated mice resulting in the suppression of the maximum peak current by 58.5 ± 15.8 pA (n = 9) and 59.2 ± 11.9 pA (n = 9), respectively. KNDy neurons appeared more sensitive to ghrelin when pretreated with EB, revealing that ARC KNDy neurons are more sensitive to ghrelin during states of high E2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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17β-Estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-Current in Female Mice

Conde¹,

Roepke²

2019

Neuroendocrinology

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“…It is likely that some degree of reciprocal communication occurs between the ARN KISS and AgRP/NPY neurones. An early brain slice study reported that kisspeptin inhibited the firing of AgRP/NPY neurones in an indirect manner, 36 whereas another found evidence for a direct glutamatergic input from ARN KISS neurones that would excite AgRP/NPY neurones at low firing rates but inhibit their activity at higher frequencies through group II metabotropic glutamatergic receptors 37,38 . Thus, directly or indirectly, ARN KISS neurones are able to suppress the activity of AgRP/NPY neurones.…”

Section: Discussionmentioning

confidence: 99%

Direct inhibition of arcuate kisspeptin neurones by neuropeptide Y in the male and female mouse

Hessler

Liu

Herbison

2020

J Neuroendocrinology

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| INTRODUC TI ONThere is a well-recognised relationship between energy status and reproduction, with either under-or over-nutrition being detrimental to fertility. 1 However, the mechanisms and pathways through which energy status suppresses the pulsatile release of luteinising hormone (LH) and gonadotrophin-releasing hormone (GnRH) remain incompletely understood. A wide variety of metabolic hormones and metabolites are implicated in modulating the frequency of the GnRH pulse generator and it is likely that multiple pathways operate in unison to achieve the appropriate pulsatile output for the nutritional status of the animal. 2,3 Foremost amongst these pathways, however, is that involving the arcuate nucleus pro-opiomelanocortin (POMC) and agouti-related peptide/neuropeptide Y (AgRP/NPY) neuronal populations that operate as metabolic sensors to control energy intake and expenditure, as well as fertility. 1,3,4 Abstract Adverse energy states exert a potent suppressive influence on the reproductive axis by inhibiting the pulsatile release of gonadotrophin-releasing hormone and luteinising hormone. One potential mechanism underlying this involves the metabolic-sensing pro-opiomelanocortin and agouti-related peptide/neuropeptide Y (AgRP/NPY) neuronal populations directly controlling the activity of the arcuate nucleus kisspeptin neurones comprising the gonadotrophin-releasing hormone pulse generator. Using acute brain slice electrophysiology and calcium imaging approaches in Kiss1-GFP and Kiss1-GCaMP6 mice, we investigated whether NPY and α-melanocyte-stimulating hormone provide a direct modulatory influence on the activity of arcuate kisspeptin neurones in the adult mouse. NPY was found to exert a potent suppressive influence upon the neurokinin B-evoked firing of approximately one-half of arcuate kisspeptin neurones in both sexes. This effect was blocked partially by the NPY1R antagonist BIBO 3304, whereas the NPY5R antagonist L152,804 was ineffective.NPY also suppressed the neurokinin B-evoked increase in intracellular calcium levels in the presence of tetrodotoxin and amino acid receptor antagonists, indicating that the inhibitory effects of NPY are direct on kisspeptin neurones. By contrast, no effects of α-melanocyte-stimulating hormone were found on the excitability of arcuate kisspeptin neurones. These studies provide further evidence supporting the hypothesis that AgRP/NPY neurones link energy status and luteinising hormone pulsatility by demonstrating that NPY has a direct suppressive influence upon the activity of a subpopulation of arcuate kisspeptin neurones. K E Y W O R D SGCaMP, GnRH, kisspeptin, neuropeptide Y, NPY receptor

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Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

Reichman

Gaynor

Monson

et al. 2019

American J of Med Genetics Pt B

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Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones.The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female-and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide. K E Y W O R D Sglutamatergic signaling, haplotype, LRRTM4, sex specificity, suicidal behavior

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Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females

Cited by 89 publications

References 87 publications

17β-Estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-Current in Female Mice

17β-Estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-Current in Female Mice

Direct inhibition of arcuate kisspeptin neurones by neuropeptide Y in the male and female mouse

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

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