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.

Mapping GABA and glutamate inputs to gonadotrophin‐releasing hormone neurones in male and female mice

“…Visualisation and quantification of apposed vesicular transporters is an effective and efficient approach for identifying morphologi- The lack of significant sex differences in morphological GABA and glutamate contacts to the GnRH neurone soma and proximal dendrite is of interest when considering previous studies that might suggest the contrary, particularly for GABA input. Prenatal androgen exposure of female mice significantly elevates both GABA activity 24,25 and GABA innervation [21][22][23] to GnRH neurones. The lack of differences identified in the present study between males and Sex differences have been identified for glutamate and GABA inputs to GnRH neurones originating from the anteroventral periventricular nucleus (AVPV), 35 an area that is sexually dimorphic and larger in females than in males.…”

“…The lack of significant sex differences in morphological GABA and glutamate contacts to the GnRH neurone soma and proximal dendrite is of interest when considering previous studies that might suggest the contrary, particularly for GABA input. Prenatal androgen exposure of female mice significantly elevates both GABA activity and GABA innervation to GnRH neurones. The lack of differences identified in the present study between males and females, using a similar morphological approach, suggest that prenatal androgenisation with the non‐aromatisable androgen dihydrotestosterone does not masculinise the GABA to GnRH neurone circuitry but instead results in an innervation pattern different to both male and healthy female controls.…”

“…In the mouse, the preovulatory surge is linked to increased GnRH neurone spine density, 15 a morphological change typically associated with increased glutamatergic input in other neuronal systems. Increased GABA inputs, [21][22][23] GABA transmission 24,25 and GnRH neurone spine density 21,22,26 are also evident in females prenatally exposed to androgens that exhibit a hyperactive GnRH axis.…”

Animal models of polycystic ovary syndrome: A review of hormone‐induced rodent models focused on hypothalamus‐pituitary‐ovary axis and neuropeptides

“…There was a significant increase in the number of kisspeptin‐ and NKB‐positive cells in the ARC of the hypothalamus in prenatal DHT‐treated rats, whereas the number of kisspeptin‐positive cells in the AVPV did not differ from that in control animals in diestrus . It was recently reported that γ‐aminobutyric acid (GABA) input to GnRH‐expressing neurons was increased in mice that were prenatally administered DHT …”

“…34 It was recently reported that γ-aminobutyric acid (GABA) input to GnRHexpressing neurons was increased in mice that were prenatally administered DHT. 37…”