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  • br Author contribution br Acknowledgement br Introduction Si

    2022-11-09


    Author contribution
    Acknowledgement
    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 GSK2334470 receptor 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.
    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 of hippocampal cultures with letrozole [14], [15]. In a recent report, we showed that systemic application of letrozole to ovariectomized female mice induced spine synapse loss in the hippocampus, underscoring the significance of locally synthesized estradiol on synaptic plasticity [16]. Studies on the role of aromatase with respect to hippocampus-related behavior are scarce (for review see: [17]). Estrogens have been demonstrated to enhance some aspects of cognitive function in animal and human models. However, the effects are often modest and inconsistent across studies (for review see: [18]). Findings from studies using the aromatase deficient mouse (ArKO) showed that GSK2334470 receptor ArKO mice of both sexes perform significantly worse than wild-type controls in tests for short-term memory [19]. In the Morris water maze test, ArKO females performed equally, if not better, than their wild-types counterparts, which may be due to the upregulation of NMDA receptors in these mutants [20]. This upregulation, however, did not occur after systemic treatment of wild-type mice with letrozole, the aromatase inhibitor [16]. Depressive-like behavior was demonstrated in ArKO mice [21], as well as an effect on the serotonin transporter, with behavioral consequences [22]. Memory deficits in women with breast cancer, and who are treated with aromatase inhibitors for therapeutical reasons, however, suggest a role of aromatase in learning and memory [23]. Bayer et al., [24] demonstrated that aromatase inhibition in women suffering from breast cancer induces hippocampus-related cognitive deficits, while no effects are observed in behavioral tasks which are related to the perirhinal cortex. Interestingly enough, letrozole treatment of mice had no effect on performance in the Morris Water maze, neither in female nor in male mice [13], while inhibition of hippocampal aromatization impairs spatial memory performance in male songbirds [25]. Rapid behavioral effects of estrogens and fast regulation of their local synthesis by brain aromatase, which shape complex behaviour, have been demonstrated, [26], [27], [28], [29]. This is a strong indication that aromatase activity also influences hippocampus-related behavior in animals.