期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：2
页码：596-601
DOI：10.1073/pnas.1415038112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePolycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility. Although the etiology of PCOS is unclear, disrupted central mechanisms mediating steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons have been suggested. We describe here, in a mouse model reflecting the clinical neuroendocrine phenotype of PCOS, evidence for disordered progesterone (P4)-sensitive GABAergic input to GnRH neurons, originating specifically within the arcuate nucleus. These discoveries define a previously unidentified neuronal pathway, potentially critical for the steroid hormone feedback control of fertility. Of clinical relevance, our findings help explain the impact of GABA agonist drugs on menstrual cycle irregularity and interference with oral contraceptives and could be the basis for understanding clinical therapies of PCOS. Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor-expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral-mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome.
