ReviewControl of aromatase in hippocampal neurons
Introduction
Since the initial finding of Gould et al. [1], showing the loss of dendritic spines in the hippocampus after ovariectomy and its rescue after treatment of the animals with estradiol, a tremendous number of studies have demonstrated a role of estradiol in synaptic plasticity and cognition in the adult, as well as during development (for review see Spencer et al. [2]). In vitro studies, aimed at estradiol-induced modulation of synaptic function, commonly apply the steroid hormone to the cultures and to gonadectomized animals, but frequently neglect neuronal estrogen synthesis. Hippocampal neurons, however, express aromatase, the final enzyme of estradiol synthesis, and these neurons have been shown to synthesize and secrete 17β-estradiol [3], [4]. The amount of estradiol in the hippocampal tissue varies with the estrus cycle and is higher in proestrus than in estrus animals, and even lower in hippocampal tissue of male animals [5], [6]. Hence, the expression and activity of aromatase is obviously controlled by, as yet, poorly defined mechanisms. For instance, in hippocampal slice cultures of female animals, application of estradiol induced spine synapse density only when hippocampal estradiol synthesis was experimentally reduced [7], [8], pointing to a cross-talk of aromatase activity in the neurons and exogenously applied estradiol.
Section snippets
Functional roles of hippocampus-derived estradiol
In the hippocampus, locally synthesized estradiol maintains hippocampal synapses [9]. Inhibition of aromatase results in a decrease in spine density, spine synapse density, the expression of synaptic proteins in female mice and in female rat hippocampal slice cultures, and impaired long term potentiation [10], [11], [12], [13] in acute and cultivated hippocampal slices. All effects could be rescued by application of estradiol [7]. Neurogenesis and axon growth are also inhibited after treatment
Activity and expression of aromatase in the hippocampus
The brain, like the adrenals, gonads and the placenta, is a steroidogenic organ. This paradigm emerged from studies carried out as early as the 1980s by Baulieu and co-workers; these studies showed that steroids such as pregnenolone and dehydroepiandrosterone were present in higher concentrations in the brain than in plasma (for review see: [30], [31], [32], [33], [34]). Furthermore, it was demonstrated that steroids persisted in the nervous system even after gonadectomy or adrenalectomy.
Regulation of hippocampal estradiol synthesis
Local concentrations of estrogens and aromatase may be classically regulated by gene transcription and enhanced protein synthesis [49], [50], [51], [52], [53], [54], [55]. We have previously shown that substrate availability and gonadotropins are potent regulators [8], [56] of estradiol synthesis. Application of testosterone, the direct substrate of aromatase, and in particular cholesterol, tremendously upregulated estradiol synthesis in hippocampal cultures [8], [57]. As a result, synapse
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