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1.
Endocrinology ; 165(7)2024 May 27.
Article in English | MEDLINE | ID: mdl-38788194

ABSTRACT

Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signaling in GABAergic neurons is critical in PCOS pathogenesis in 2 well-characterized hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic peripubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to gonadotropin-releasing hormone (GnRH) neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy, and impaired glucose homeostasis, was not different between GABARKO and wild-type (WT) mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinizing hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signaling in GABA neurons is largely not required for the development of PCOS-like traits in androgenized models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signaling in GABA neurons.


Subject(s)
Disease Models, Animal , GABAergic Neurons , Hyperandrogenism , Mice, Knockout , Polycystic Ovary Syndrome , Receptors, Androgen , Animals , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/genetics , Female , Receptors, Androgen/metabolism , Receptors, Androgen/genetics , Mice , GABAergic Neurons/metabolism , Hyperandrogenism/metabolism , Hyperandrogenism/genetics , Ovary/metabolism , Androgens/metabolism , Pregnancy , Gonadotropin-Releasing Hormone/metabolism , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/genetics
2.
Sci Rep ; 6: 21101, 2016 Feb 16.
Article in English | MEDLINE | ID: mdl-26879842

ABSTRACT

In Alzheimer's disease (AD), there is a loss in cholinergic innervation targets of basal forebrain which has been implicated in substantial cognitive decline. Amyloid beta peptide (Aß(1-42)) accumulates in AD that is highly toxic for basal forebrain cholinergic (BFC) neurons. Although the gonadal steroid estradiol is neuroprotective, the administration is associated with risk of off-target effects. Previous findings suggested that non-classical estradiol action on intracellular signaling pathways has ameliorative potential without estrogenic side effects. After Aß(1-42) injection into mouse basal forebrain, a single dose of 4-estren-3α, 17ß-diol (estren), the non-classical estradiol pathway activator, restored loss of cholinergic cortical projections and also attenuated the Aß(1-42)-induced learning deficits. Estren rapidly and directly phosphorylates c-AMP-response-element-binding-protein and extracellular-signal-regulated-kinase-1/2 in BFC neurons and restores the cholinergic fibers via estrogen receptor-α. These findings indicated that selective activation of non-classical intracellular estrogen signaling has a potential to treat the damage of cholinergic neurons in AD.


Subject(s)
Amyloid beta-Peptides/metabolism , Basal Forebrain/metabolism , Cholinergic Fibers/metabolism , Estrogens/metabolism , Peptide Fragments/metabolism , Signal Transduction , Amyloid beta-Peptides/pharmacology , Animals , Basal Forebrain/drug effects , Basal Forebrain/pathology , Cell Count , Cholinergic Fibers/drug effects , Cholinergic Fibers/pathology , Cholinergic Neurons/drug effects , Cholinergic Neurons/metabolism , Cholinergic Neurons/pathology , Estrogen Receptor alpha/metabolism , Estrogens/pharmacology , Female , Learning/drug effects , Mice , Mice, Knockout , Peptide Fragments/pharmacology , Phosphorylation , Signal Transduction/drug effects , Somatosensory Cortex/drug effects , Somatosensory Cortex/metabolism , Somatosensory Cortex/pathology
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