Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS
Mauro S.B. Silva, Melanie Prescott, Rebecca E. Campbell
Mauro S.B. Silva, Melanie Prescott, Rebecca E. Campbell
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Research Article Endocrinology Neuroscience

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

Abstract

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP–transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

Authors

Mauro S.B. Silva, Melanie Prescott, Rebecca E. Campbell

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Figure 3

Blockade of androgen receptor (AR) signaling reverses GABA-to-GnRH circuit abnormalities in adult PNA mice.

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Blockade of androgen receptor (AR) signaling reverses GABA-to-GnRH circu...
(A) Confocal images of adult diestrus control and prenatally androgenized (PNA) mice showing GnRH-GFP neurons (green) and vesicular GABA transporter–immunoreactive (VGAT-ir) contacts representing GABA inputs (red puncta) in the rostral preoptic area. Red puncta (VGAT-ir) in close apposition to green GnRH neurons can appear as yellow or with a yellow halo as a result of overlap in confocal projections. White arrowheads indicate putative GABAergic inputs to GnRH neurons. Scale bars: 10 μm. (B and E) Projected 3D reconstruction of a GnRH-GFP neuron from an adult PNA mouse illustrating VGAT-ir puncta contacts, with white arrowheads indicating VGAT contact onto non-spiny GnRH neuron membrane, and blue arrowheads indicating inputs onto somatic and dendritic spines. Rotated and zoomed inset images of VGAT contact with a somatic spine (C), front and back views of dendritic spines in the distal dendrite covered with GABA inputs (D and F), and VGAT contacts onto the proximal dendrite of a GnRH neuron (G). (H) Total VGAT-ir density on GnRH neurons of control+oil (N = 6; 61 neurons), control+Flut (N = 7; 72 neurons), PNA+oil (N = 5; 53 neurons), and PNA+Flut (N = 7; 72 neurons) groups. VGAT appositions are shown for each neuronal compartment. (I) Total VGAT apposition density onto non-spiny GnRH neuron membrane. (J) Total VGAT-ir apposition density onto GnRH neuron spines. (K) Number of GnRH neuron spines. Histogram values are represented by mean ± SEM with dot plots of individual values. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.01; 2-way ANOVA with Tukey’s post hoc test. Flut, flutamide; GnRH, gonadotropin-releasing hormone.