Sex steroids and the dentate gyrus

Abstract

In the late 1980s, the finding that the dentate gyrus contains more granule cells in the male than in the female of certain mouse strains provided the first indication that the dentate gyrus is a significant target for the effects of sex steroids during development. Gonadal hormones also play a crucial role in shaping the function and morphology of the adult brain. Besides reproduction-related processes, sex steroids participate in higher brain operations such as cognition and mood, in which the hippocampus is a critical mediator. Being part of the hippocampal formation, the dentate gyrus is naturally involved in these mechanisms and as such, this structure is also a critical target for the activational effects of sex steroids. These activational effects are the results of three major types of steroid-mediated actions. Sex steroids modulate the function of dentate neurons under normal conditions. In addition, recent research suggests that hormone-induced cellular plasticity may play a larger role than previously thought, particularly in the dentate gyrus. Specifically, the regulation of dentate gyrus neurogenesis and synaptic remodeling by sex steroids received increasing attention lately. Finally, the dentate gyrus is influenced by gonadal hormones in the context of cellular injury, and the work in this area demonstrates that gonadal hormones have neuroprotective potential. The expression of estrogen, progestin, and androgen receptors in the dentate gyrus suggests that sex steroids, which could be of gonadal origin and/or synthesized locally in the dentate gyrus, may act directly on dentate cells. In addition, gonadal hormones could also influence the dentate gyrus indirectly, by subcortical hormone-sensitive structures such as the cholinergic septohippocampal system. Importantly, these three sex steroid-related themes, functional effects in the normal dentate gyrus, mechanisms involving neurogenesis and synaptic remodeling, as well as neuroprotection, have substantial implications for understanding normal cognitive function, with clinical importance for epilepsy, Alzheimer's disease and mental disorders.

Figure 1

Effects of ovariectomy and estrogen replacement on the number of hippocampal spine synapses. Young adult female Sprague-Dawley rats (250 g) were ovariectomized and one week later, they received either 10 μg/rat/day estradiol-benzoate (EB, solid columns) or 200 μl/rat/day sesame oil vehicle (Oil, open columns) subcutaneously for two days. Two days after the last injection, the animals were sacrificed by transcardial perfusion of fixative, and their brains were processed for electron microscopic stereological analysis. Spine synapses were counted in the CA1 and CA3 strata radiata, and in the molecular layer of the dentate gyrus (DG). *Significantly different from the corresponding Oil group (t-test, p<0.001 in CA1 and DG, p<0.01 in CA3).

Figure 2

Subcellular localization of estrogen (ER), androgen (AR) and progestin (PR) receptors in the dentate gyrus. A subset of GABAergic interneurons contains nuclear ERα (dark pink). Granule cells, newly born cells (identified by DCX) and some GABAergic interneurons contain cytosolic and plasma membrane-associated ERβ (blue). Dendritic spines, many originating from granule cells contain ERα, ERβ, AR (dark green) and PR (purple). A few dendritic spines in the hilus, likely originating from mossy cells, contain ERα and ERβ. ERα, ERβ, AR and PR are found in axons and axon terminals. Some ERα-containing terminals are cholinergic (acetylcholine, orange); some ERβ-containing terminals resemble monoaminergic boutons. Lot of astrocytes (stars), mostly in the molecular layer, also contain ERα, ERβ, AR and PR.