Unusual suspects: Glial cells in fertility regulation and their suspected role in polycystic ovary syndrome

Abstract

Gonadotropin-releasing-hormone (GnRH) neurons sitting within the hypothalamus control the production of gametes and sex steroids by the gonads, therefore ensuring survival of species. As orchestrators of reproductive function, GnRH neurons integrate information from external and internal cues. This occurs through an extensively studied neuronal network known as the "GnRH neuronal network." However, the brain is not simply composed of neurons. Evidence suggests a role for glial cells in controlling GnRH neuron activity, secretion and fertility outcomes, although numerous questions remain. Glial cells have historically been seen as support cells for neurons. This idea has been challenged by the discovery that some neurological diseases originate from glial dysfunction. The prevalence of infertility disorders is increasing worldwide, with one in four couples being affected; therefore, it remains essential to understand the mechanisms by which the brain controls fertility. The "GnRH glial network" could be a major player in infertility disorders and represent a potential therapeutic target. In polycystic ovary syndrome (PCOS), the most common infertility disorder of reproductive aged women worldwide, the brain is considered a prime suspect. Recent studies have demonstrated pathological neuronal wiring of the "GnRH neuronal network" in PCOS-like animal models. However, the role of the "GnRH glial network" remains to be elucidated. In this review, I aim to propose glial cells as unusual suspects in infertility disorders such as PCOS. In the first part, I state our current knowledge about the role of glia in the regulation of GnRH neurons and fertility. In the second part, based on our recent findings, I discuss how glial cells could be implicated in PCOS pathology.

Keywords: GnRH; PCOS; astrocyte; fertility; glia; microglia; tanycyte.

FIGURE 1

Role of glial cells in fertility regulation. (A) Schematic of the hypothalamic‐pituitary‐gonadal (HPG) axis: gonadotropin‐releasing hormone (GnRH) neurons (red) secrete GnRH within the portal blood to stimulate gonadotropin secretion by the pituitary. Then, luteinising hormone (LH) and follicle‐stimulating hormone (FSH) target the ovaries to trigger the production of gametes and sex steroid hormones. These sex hormones then feedback to the GnRH neurons via the “GnRH neuronal network.” Glial cells (blue) are observed in the vicinity of the GnRH neurons and nerve terminals and play a role in the regulation of GnRH secretion. (B) Role of glial cells around the GnRH soma: during the basal pulsatile GnRH secretion phase, glial cells (blue) enwrap GnRH neurons (red), blocking inputs (black); however, preceding the preovulatory GnRH surge, glial processes allow the GnRH neuronal networks inputs to connect to GnRH neurons, therefore triggering a GnRH surge. (C) Role of glial cells in the vicinity of GnRH nerve terminals: during the basal pulsatile GnRH secretion phase, glial cells (blue), mostly tanycyte end‐feets, enwrap GnRH nerve terminals (red) to block their access to portal blood capillaries (brown); however, at the time of the preovulatory surge, tanycyte end‐feets retract, allowing GnRH nerve terminals to access the portal blood capillaries, leading to high secretion of GnRH (i.e., the preovulatory surge). GnRH‐N, gonadotropin‐releasing hormone neurons

FIGURE 2

Communication between gonadotropin‐releasing hormone (GnRH) neurons and glial cells. Numerous signaling molecules are involved in the communication between glial cells and GnRH neurons (GnRH‐N). The following molecules have been shown to contribute to the regulation of GnRH secretion by astrocytes and tanycytes: the adhesion molecules synaptic cell adhesion molecule 1 (SynCAM1) and neural cell adhesion molecule (NCAM), as well as some glial factors and their receptors such as prostaglandin E2 (PDGE2), transforming growth factor α (TGFα) and neuregulin (NRG), and their receptors, respectively, EP1/2 and ErbBs (ErbB1/2 or ErbB2/4). COX2, cyclooxygenase 2; MMP, matrix metalloproteinase

FIGURE 3

Physical interaction between gonadotropin‐releasing hormone (GnRH) neurons, microglia and astrocytes in the mouse brain during development (A) and adulthood (B). (A) Microglia (CX1CR3‐GFP, yellow) are in close association with the soma and dendrites of a GnRH neuron (GnRH‐immunoreactivity, red) within the rostral preoptic area at postnatal day 15 in mice. In this 3D reconstruction from confocal micrographs, one of the microglia filopodia (yellow) enwraps the GnRH dendrite (red) (images adapted from Sati et al. ²² ). (B) Microglia (IBA‐1 immunoreactivity, yellow) are also found in the vicinity of GnRH neurons soma and dendrites (GnRH‐immunoreactivity, red) in the rostral preoptic area at adulthood. In this representative single focal plan (z = …) taken by a confocal microscope, we observe that microglia (yellow) are not only in the vicinity of GnRH neurons, but also in close association. Interestingly, we can observe that astrocyte (Aldh1L1‐cre/dTomato, cyan) are also in close association with both GnRH neurons (GnRH‐immunoreactivity, red) and microglia (IBA‐1‐immunoreactivity, yellow) (E. Desroziers, unpublished results). PND, postnatal day

FIGURE 4

Unravelling the role of glial cells in polycystic ovary syndrome (PCOS)‐pathological regulation of fertility. Schematic illustrating current knowledge on the role of the brain in the regulation of the hypothalamic‐pituitary‐gonadal (HPG) axis in PCOS. In PCOS, an increase pulsatile secretion of luteinising hormone (LH) and lower secretion of follicle‐stimulating hormone (FSH) has been observed, mirroring a hyperactivity of gonadotropin releasing hormone neurons (GnRH‐N) (red), leading to the three cardinal features of PCOS: high circulating level of androgens, polycystic ovaries and oligo/anovulation. Impaired sex hormone feedback has also been observed in patients with PCOS. Animal‐based models have allowed to investigate the role of the brain in this disruption of the HPG axis. It has been observed that GABA neurons coming from the arcuate nucleus (ARN GABA‐N, green) are less sensitive to at least one sex hormone and send more projections to the GnRH neurons, leading to the hypersecretion of GnRH/LH. We now wonder whether glial cells (blue) could play a major role in the PCOS pathophysiology. ARN GABA‐N, GABA‐N located in the arcuate nucleus

FIGURE 5

Role of microglia in polycystic ovary syndrome (PCOS) pathology. Schematic illustrating our recent findings on the role of microglia in PCOS. (A) Microglia are shaping the developing PCOS brain: recent evidence showed that microglia (yellow) engulf (i.e., eat) GABAergic inputs (green) in the vicinity of the soma of gonadotropin‐releasing hormone (GnRH) neurons (red); however, in the PCOS condition, microglia engulf/eat less GABAergic inputs, leading to the observed increase in GABAergic inputs at adulthood. (B) Is there inflammation in the adult PCOS brain? Our current results show a subtle increase of the inflammatory microglia phenotype (i.e., ameboid microglia) (yellow) in the vicinity of the soma of GnRH neurons (red), suggesting a potential inflammatory status in the prenatally‐androgenised mouse model of PCOS; however, further investigations are still needed to draw any conclusions