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

Cristina Sáenz de Miera; Nicole Bellefontaine; Susan J Allen; Martin G Myers; Carol F Elias

doi:10.7554/eLife.93204

eLife (Jul 2024)

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

Cristina Sáenz de Miera,
Nicole Bellefontaine,
Susan J Allen,
Martin G Myers,
Carol F Elias

Affiliations

Cristina Sáenz de Miera: ORCiD; Department of Molecular and Integrative Physiology, University of Michigan–Ann Arbor, Ann Arbor, United States
Nicole Bellefontaine: Department of Molecular and Integrative Physiology, University of Michigan–Ann Arbor, Ann Arbor, United States
Susan J Allen: Department of Molecular and Integrative Physiology, University of Michigan–Ann Arbor, Ann Arbor, United States
Martin G Myers: Department of Molecular and Integrative Physiology, University of Michigan–Ann Arbor, Ann Arbor, United States; Elizabeth W. Caswell Diabetes Institute, University of Michigan–Ann Arbor, Ann Arbor, United States; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan–Ann Arbor, Ann Arbor, United States
Carol F Elias: ORCiD; Department of Molecular and Integrative Physiology, University of Michigan–Ann Arbor, Ann Arbor, United States; Elizabeth W. Caswell Diabetes Institute, University of Michigan–Ann Arbor, Ann Arbor, United States; Department of Obstetrics and Gynecology, University of Michigan–Ann Arbor, Ann Arbor, United States

DOI: https://doi.org/10.7554/eLife.93204
Journal volume & issue: Vol. 13

Abstract

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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 long form (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determined the role of glutamatergic neurotransmission from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces luteinizing hormone (LH) release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LeprCre (LepRb-Cre) mice. We collected blood sequentially before and for 1 hr after intravenous clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of Fos immunoreactive neurons in the PMv. Next, females with deletion of Slc17a6 (Vglut2) in LepRb neurons (LeprΔVGlut2) showed delayed age of puberty, disrupted estrous cycles, increased gonadotropin-releasing hormone (GnRH) concentration in the axon terminals, and disrupted LH secretion, 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 Slc17a6 (Vglut2flox) mice. Rescue of Lepr and deletion of Slc17a6 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LeprloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation, and became pregnant, while LeprloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic neurotransmission from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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