Review
Control of aromatase in hippocampal neurons

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Highlights

  • Estradiol is synthesized in hippocampal neurons.

  • Aromatase in hippocampal neurons becomes phoshorylated upon treatment of the neurons with estradiol.

  • Estradiol release from hippocampal neurons is stimulated by depletion of Ca2+ stores using thapsigargin.

  • Aromatase protein is upregulated upon treatment of hippocampal neurons with estradiol.

Abstract

Our knowledge on estradiol-induced modulation of synaptic function in the hippocampus is widely based on results following the application of the steroid hormone to either cell cultures, or after the treatment of gonadectomized animals, thus ignoring local neuronal estrogen synthesis. We and others, however, have shown that hippocampus-derived estradiol also controls synaptic plasticity in the hippocampus. Estradiol synthesis in the hippocampus is regulated by several mechanisms, which are reviewed in this report. The regulation of the activity of aromatase, the final enzyme of estrogen biosynthesis, by Ca2+ transients, is of particular interest. Aromatase becomes inactivated as soon as it is phosphorylated by Ca2+-dependent kinases upon calcium release from internal stores. Accordingly, thapsigargin dephosphorylates aromatase and stimulates estradiol synthesis by depletion of internal Ca2+ stores. Vice versa, letrozole, an aromatase inhibitor, phosphorylates aromatase and reduces estradiol synthesis. Treatment of the cultures with 17β-estradiol results in phosphorylation of the enzyme and increased aromatase protein expression, which suggests that estradiol synthesis in hippocampal neurons is regulated in an autocrine manner.

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

References (76)

  • D.S. Reddy

    Neurosteroids: endogenous role in the human brain and therapeutic potentials

    Prog. Brain Res.

    (2010)
  • E.E. Baulieu et al.

    Neurosteroids: a new brain function?

    J. Steroid Biochem. Mol. Biol.

    (1990)
  • K. Shibuya et al.

    Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction

    Biochim. Biophys. Acta

    (2003)
  • N.J. MacLusky et al.

    Aromatase in the cerebral cortex, hippocampus, and mid-brain: ontogeny and developmental implications

    Mol. Cell. Neurosci.

    (1994)
  • C. Beyer et al.

    Aromatase-immunoreactive neurons in the adult female chicken brain detected using a specific antibody

    Brain Res. Bull.

    (1994)
  • J.G. Yague et al.

    Aromatase expression in the human temporal cortex

    Neuroscience

    (2006)
  • J.G. Yague et al.

    Aromatase distribution in the monkey temporal neocortex and hippocampus

    Brain Res.

    (2008)
  • L.M. Garcia-Segura et al.

    Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair

    Neuroscience

    (1999)
  • T.A. Ishunina et al.

    Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer’s disease

    Neurobiol. Aging

    (2007)
  • N. Harada et al.

    Synergism between androgens and estrogens in the induction of aromatase and its messenger RNA in the brain

    Brain Res.

    (1993)
  • S. Iivonen et al.

    Effects of estradiol on spatial learning, hippocampal cytochrome P450 19, and estrogen alpha and beta mRNA levels in ovariectomized female mice

    Neuroscience

    (2006)
  • T.W. Miller et al.

    Aromatase is phosphorylated in situ at serine-118

    J. Steroid Biochem. Mol. Biol.

    (2008)
  • J. Balthazart et al.

    Phosphorylation processes mediate rapid changes of brain aromatase activity

    J. Steroid Biochem. Mol. Biol.

    (2001)
  • J. Balthazart et al.

    Is brain estradiol a hormone or a neurotransmitter?

    Trends Neurosci.

    (2006)
  • J. Lytton et al.

    Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps

    J. Biol. Chem.

    (1991)
  • L. Zhao et al.

    17beta-estradiol induces Ca2+ influx, dendritic and nuclear Ca2+ rise and subsequent cyclic AMP response element-binding protein activation in hippocampal neurons: a potential initiation mechanism for estrogen neurotrophism

    Neuroscience

    (2005)
  • J. Prange-Kiel et al.

    Endocrine regulation of estrogen synthesis in the hippocampus?

    Prog. Histochem. Cytochem.

    (2013)
  • N. Emptage et al.

    Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines

    Neuron

    (1999)
  • E. Gould et al.

    Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood

    J. Neurosci.

    (1990)
  • J. Prange-Kiel et al.

    Para/autocrine regulation of estrogen receptors in hippocampal neurons

    Hippocampus

    (2003)
  • Y. Hojo et al.

    Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017 alpha and P450 aromatase localized in neurons

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • A. Kato et al.

    Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines

    Front. Neural Circuits

    (2013)
  • L. Fester et al.

    Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus

    Hippocampus

    (2009)
  • O. Kretz et al.

    Hippocampal synapses depend on hippocampal estrogen synthesis

    J. Neurosci.

    (2004)
  • R. Vierk et al.

    Aromatase inhibition abolishes LTP generation in female but not in male mice

    J. Neurosci.

    (2012)
  • S. Grassi et al.

    Influence of visual experience on developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei

    J. Physiol.

    (2004)
  • V.E. Pettorossi et al.

    Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats

    Physiol. Rep.

    (2013)
  • J. Vierk et al.

    Structure–function–behavior relationship in estrogen-induced synaptic plasticity

    Horm. Behav.

    (2015)
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