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Publication
Glutamate neurotransmission from leptin receptor cells is required for typical
puberty and reproductive function in female mice.
Authors Sáenz de Miera C, Bellefontaine N, Allen SJ, Myers MG, Elias CF
Submitted By Submitted Externally on 10/15/2024
Status Published
Journal eLife
Year 2024
Date Published 7/1/2024
Volume : Pages 13 : Not Specified
PubMed Reference 39007235
Abstract 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 (Lepr?VGlut2) 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.




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