Endocrine regulation of estrogen synthesis in the hippocampus?

Abstract

Estradiol synthesis in the ovaries is regulated via feedback mechanisms mediated by gonadotrophin-releasing hormone (GnRH) and gonadotrophins, secreted by the hypothalamus and the pituitary, respectively. Estradiol synthesis also takes place in the hippocampus. In hippocampal slice cultures of female animals, GnRH regulates estradiol synthesis dose-dependently. Hence, both hippocampal and ovarian estradiol synthesis are synchronized by GnRH. Hippocampus-derived estradiol is essential to synapse stability and maintenance because it stabilizes the spine cytoskeleton of hippocampal neurons. Inhibition of hippocampal estradiol synthesis in mice, however, results in loss of spines and spine synapses in females, but not in males. Stereotaxic application of GnRH to the hippocampus of female rats confirms the regulatory role of GnRH on estradiol synthesis and synapse density in the female hippocampus in vivo. This regulatory role of GnRH necessarily results in estrus cyclicity of spine density in the hippocampus of females.

Introduction

It has long been known that hormones, namely estrogens, influence synaptic plasticity. In the early 1990s, McEwen and co-workers showed in rodents that the removal of ovaries induces a loss of postsynaptic dendritic spines on hippocampal neurons of the CA1 region (Gould et al., 1990). Systemic injections of estradiol into these animals rescued this effect, and it was thus concluded that estradiol originating from the ovaries influences spine density in the hippocampus. Circulating sex hormones can easily penetrate into the hippocampus by crossing the blood brain barrier. At the same time, it was also shown that in female rats, spine density varies with the estrous cycle, corroborating the hypothesis that ovary-derived estradiol in serum controls spine density in the hippocampus (Woolley et al., 1990). When serum estradiol concentrations are at their highest at proestrus, shortly before ovulation, spine density reaches its maximum and the density of spines decreases thereafter, along with decreasing levels of estradiol in serum. Application of estradiol to hippocampal slice cultures, thus in the absence of any other source of estradiol, however, failed to induce spine synapse formation (Kretz et al., 2004). Neither physiological serum concentrations of estradiol nor high doses of estradiol increase the number of spine synapses, thus questioning the role of ovarian estradiol on spine density in the hippocampus.

In view of the failure of estradiol to induce spine formation in hippocampal slice cultures, it should be considered that the brain, like the adrenals, gonads, and the placenta, is a steroidogenic organ. This paradigm emerged from studies, showing that steroids such as pregnenolone and dihydroepiandrosterone were present in higher concentrations in the brain than in plasma (for review see: Baulieu et al., 2001, Mellon and Griffin, 2002, Do Rego et al., 2009, Pelletier, 2010, Reddy, 2010). Furthermore, it was demonstrated that steroids persist in the nervous system after gonadectomy or adrenalectomy. Accordingly, neurosteroids are defined as steroids that accumulate in the brain, even in the absence of steroidogenic glands, and are synthesized in the brain from endogenous precursors by enzymes that are present in situ (Baulieu and Robel, 1990). Sex steroids, such as estradiol and testosterone, are not classically considered to be brain-derived neurosteroids as, for a long time, it was not possible to demonstrate the synthesis of their precursors, dehydroepiandrosterone and androstendione. In these earlier studies, the main focus was on the synthesis of pregnenolone and its function in the nervous system, rather than on the synthesis of sex steroids, such as estradiol and testosterone. Meanwhile, it has been widely established that the brain, including the hippocampus, is equipped with all the enzymes necessary for steroidogenesis (for review see: Oishi et al., 2012).