<scp>KNDy</scp>neurones and<scp>GnRH</scp>/<scp>LH</scp>pulse generation: Current understanding and future aspects

Uenoyama, Yoshihisa; Tsukamura, Hiroko

doi:10.1111/jne.13285

“…We did not observe alterations in gonadotropin expression in the pituitary gland, but we found a reduction in Tac2 levels, coding for Neurokinin B, in the hypothalamus of LepRb-cre ΔVglut2 females. These findings indicate that blockade of glutamatergic neurotransmission in LepRb neurons disrupts key components of the GnRH pulse generator (Han et al, 2023 ;Ruka et al, 2013 ;Uenoyama and Tsukamura, 2023 ), leading ultimately to reproductive deficits.…”

Section: Discussionmentioning

confidence: 93%

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

de Miera,

Bellefontaine,

Allen

et al. 2024

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The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determine the role of glutamatergic signaling from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces LH release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LepRb-Cre mice. We collected blood sequentially before and for 1h after iv. clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of cFos immunoreactive neurons in the PMv. Next, females with deletion of Vglut2 in LepRb neurons (LepR Δ VGlut2 ) showed delayed age of puberty, disrupted estrous cycles, increased GnRH concentration in the axon terminals and disrupted LH responses, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LepR loxTB ) with concomitant deletion of Vglut2 ( Vglut2 -floxed) mice. Rescue of Lepr and deletion of Vglut2 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LepR loxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation and became pregnant, while LepR loxTB ; Vglut2 flox mice showed no pubertal development. Our results indicate that glutamatergic signaling from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2. Age of puberty and reproductive function are strongly influenced by energy balance. Leptin is the primary metabolic hormone in reproductive control, but the neural circuitry involved is not fully understood. Previous studies have suggested that GABAergic but not glutamatergic neurotransmission is required for leptin action on reproduction. However, the PMv, a nucleus essential for the metabolic control of the reproductive function, densely expresses Lepr and is essentially glutamatergic. Here we show that remote activation of leptin-responsive neurons in the PMv induces LH secretion, while deletion of glutamatergic neurotransmission in LepR (or PMv) neurons disrupts pubertal development and impairs the reproductive function in female mice. Our findings indicate that glutamate in LepR, and specifically in PMv, neurons is required for reproductive maturation and function.

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“…We did not observe alterations in gonadotropin expression in the pituitary gland, but we found a reduction in Tac2 levels, coding for Neurokinin B, in the hypothalamus of LepRb-cre Δ Vglut2 females. These findings indicate that blockade of glutamatergic neurotransmission in LepRb neurons disrupts key components of the GnRH pulse generator (Han et al, 2023; Ruka et al, 2013; Uenoyama and Tsukamura, 2023), leading ultimately to reproductive deficits.…”

Section: Discussionmentioning

confidence: 95%

“…We did not observe alterations in gonadotropin expression in the pituitary gland, but we found a reduction in Tac2 levels, coding for Neurokinin B (NKB), in the hypothalamus of LepRb-cre Δ Vglut2 females. These findings indicate that blockade of glutamatergic neurotransmission in LepRb neurons disrupts key components of the GnRH pulse generator (Han et al, 2023; Ruka et al, 2013; Uenoyama and Tsukamura, 2023), leading ultimately to reproductive deficits. Indeed, previous research showed that activation of the Neurokinin 3 receptor (NK3R) by an NKB agonist induced GnRH release consistently from the ME even in kisspeptin knockout animals, but not the preoptic region where GnRH cell bodies are located (Gaskins et al, 2013), suggesting that Tac2 alone could be a direct mediator of the glutamatergic effect on GnRH release.…”

Section: Discussionmentioning

confidence: 95%

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

Sáenz de Miera,

Bellefontaine,

Allen

et al. 2023

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The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determine the role of glutamatergic signaling from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces LH release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LepRb-Cre mice. We collected blood sequentially before and for 1h after iv. clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of cFos immunoreactive neurons in the PMv. Next, females with deletion ofVglut2in LepRb neurons (LepRΔVglut2) showed delayed age of puberty, disrupted estrous cycles, increased GnRH concentration in the axon terminals and disrupted LH responses, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LepRloxTB) with concomitant deletion of Vglut2 (Vglut2-floxed) mice. Rescue of Lepr and deletion of Vglut2 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LepRloxTBmice with PMv LepRb rescue showed vaginal opening, follicle maturation and became pregnant, while LepRloxTB;Vglut2floxmice showed no pubertal development. Our results indicate that glutamatergic signaling from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.

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“…The HPG axis, a neuroendocrine system, plays a role in reproduction by regulating LH/FSH and sex steroid secretion. The KNDy pathway is also linked to reproductive function [ 32 ]. In our research, we studied the genetics of the PDYN / OPRK1 complex; however, no mutations were found.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants in KNDy Pathway Lack Association with Premature Ovarian Insufficiency in Mexican Women: A Sequencing-Based Cohort Study

Ruiz,

Ramos

2024

Genes

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Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity of the hypothalamic–pituitary–gonadal axis. Identified loss-of-function mutations in these genes are linked to various reproductive disorders. This study investigated genetic disorders linked to mutations in the KNDy genes related to premature ovarian insufficiency (POI). A cohort of 14 Mexican POI patients underwent genetic screening using PCR-SSCP and Sanger sequencing, assessing the genetic variations’ impact on protein function thereafter using multiple in silico tools. The PCR excluded extensive deletions, insertions, and duplications, while SSCP detected five genetic variants. Variations occurred in the KISS1 (c.58G>A and c.242C>G), KISS1R (c.1091A>T), PDYN (c.600C>T), and OPRK1 (c.36G>T) genes, whereas no genetic anomalies were found in NK3/NK3R genes. Each single-nucleotide variant underwent genotyping using PCR-SSCP in 100 POI-free subjects. Their allelic frequencies paralleled the patient group. These observations indicate that allelic variations in the KNDy genes may not contribute to POI etiology. Hence, screening for mutations in KNDy genes should not be a part of the diagnostic protocol for POI.

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KNDyneurones andGnRH/LHpulse generation: Current understanding and future aspects

Cited by 14 publications

References 231 publications

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

Genetic Variants in KNDy Pathway Lack Association with Premature Ovarian Insufficiency in Mexican Women: A Sequencing-Based Cohort Study

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