Estrogen-regulated synaptogenesis in the hippocampus: Sexual dimorphism in vivo but not in vitro

Fester, Lars; Prange‐Kiel, Janine; Zhou, Lepu; Blittersdorf, Breda v.; Böhm, Julia; Jarry, Hubertus; Schumacher, Michaël; Rune, Gabriele M.

doi:10.1016/j.jsbmb.2011.11.010

Cited by 96 publications

(83 citation statements)

References 30 publications

(49 reference statements)

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“…In contrast, the number of spine synapses and the number of mature spines were unchanged in males and were very much consistent, with no change in LTP. Consistent with the in vitro data on spine density on male single neurons and spine synapse density in male hippocampal slice cultures in response to letrozole, systemic treatment of male adult animals with the aromatase inhibitor had no effect, even after 4 weeks of treatment with letrozole (Zhou et al, 2010;Fester et al, 2012).…”

Section: Local Estradiol Synthesis Controls Spine Synapse Density In supporting

confidence: 81%

“…When we compared the amount of estradiol synthesis in dissociated cultures that originated from male animals with cultures that originated from female animals, no difference was found in the amount of estradiol in the supernatant, as evidenced by radioimmunoassay (Fester et al, 2012).…”

Section: Hippocampal Neurons Synthesize Estradiol Independent Of Gendermentioning

confidence: 94%

“…This dependency could also help to understand why the content of estradiol in hippocampal tissue as measured by mass spectrometry differs between males and proestrus females (Fester et al, 2012), although the capacity of estradiol synthesis in dissociated single hippocampal neurons does not differ between males and females. Robust functional sex differences have been identified in hypothalamic circuitry regulating reproductive function.…”

Section: How Can the Estrus Cyclicity Of Synaptogenesis In Females Bementioning

confidence: 99%

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Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus

Brandt

Vierk²,

Rune³

2013

Int. J. Dev. Biol.

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It has long been known that estradiol influences synaptic plasticity in the female hippocampus. The density of dendritic spines varies during the estrous cycle and correlates positively with varying levels of estradiol in serum. In accordance, ovariectomy results in a loss of spines that can be rescued by estradiol treatment in animals, suggesting that estradiol originating from the ovaries induces spine formation in the hippocampus. More recent studies point to a role of hippocampusderived estradiol in synaptogenesis in the female hippocampus, rather than of estradiol of ovarian origin. In our studies, we have shown that inhibition of hippocampal estrogen synthesis results in spine synapse loss in female animals and, more importantly, also in ovariectomized animals. Surprisingly, inhibition of local estradiol synthesis had no effect on synapse formation in males, in spite of a similar capacity to synthesize estradiol in male and female hippocampal neurons. In females, neuro-sexual steroid production is promoted by hypothalamic, cyclic GnRH release and likely underlies the estrus cyclicity of spine synapse density in the hippocampus. As a result, peripheral serum concentrations of estradiol determine the amount of estradiol synthesis in the hippocampus. This paradigm may also be true in males. In support of this hypothesis, we found that the content of estradiol in hippocampal tissue is higher in female compared to that in male animals, with low levels of estradiol in serum and tonic and acyclical GnRH release. In summary, our data point to important sex-specific differences in sexual steroid-induced synaptogenesis.

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Section: Local Estradiol Synthesis Controls Spine Synapse Density In supporting

confidence: 81%

Section: Hippocampal Neurons Synthesize Estradiol Independent Of Gendermentioning

confidence: 94%

Section: How Can the Estrus Cyclicity Of Synaptogenesis In Females Bementioning

confidence: 99%

See 1 more Smart Citation

Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus

Brandt

Vierk²,

Rune³

2013

Int. J. Dev. Biol.

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“…Mature spines are considerably reduced in response to letrozole in female neurons but are unaffected in male neurons. Moreover, spine synapse density is generally lower in male than in female hippocampi, consistent with lower estradiol concentrations in hippocampal tissue of males than of females (Fester et al, 2011). In sum, differences between genders in the regulation of synaptic plasticity in response to sexual steroids show that inhibition of aromatase specifically affects synaptic plasticity in females but not in males.…”

Section: Spine Synapse Loss In Females But Not In Malesmentioning

confidence: 55%

“…3B). Notably, LTP was not impaired after ovariectomy alone, although ovariectomy substantially reduces estradiol concentrations in serum (Fester et al, 2011). Thus, estradiol of ovarian origin does not seem to play a role in hippocampal LTP.…”

Section: Aromatase Inhibition Impairs Ltpmentioning

confidence: 86%

Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

Vierk

Glassmeier²,

Zhou³

et al. 2012

Journal of Neuroscience

149

137

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Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.

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Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus

Eagleson

Milner

Xie³

et al. 2013

J of Comparative Neurology

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MET, a replicated autism risk gene, encodes a pleiotropic receptor tyrosine kinase implicated in multiple cellular processes during development and following injury. Previous studies suggest that Met modulates excitatory synapse development in the neocortex and hippocampus, although the underlying mechanism is unknown. The peak of Met expression corresponds to the period of process outgrowth and synaptogenesis, with robust expression in hippocampal and neocortical neuropil. Resolving whether neuropil expression represents presynaptic, postsynaptic or glial localization provides insight into potential mechanisms of Met action. The subcellular distribution of Met was characterized using complementary ultrastructural, in situ proximity ligation assay (PLA) and biochemical approaches. At postnatal day (P) 7, immuno-electron microscopy revealed near-equivalent proportions of Met-immunoreactive pre- (axons and terminals) and post- (dendritic shafts and spines) synaptic profiles in the stratum radiatum in the hippocampal CA1 region. Staining was typically in elements in which the corresponding pre- or postsynaptic apposition was unlabeled. By P21, Met-immunoreactive presynaptic profiles predominated and approximately 20% of Met-expressing profiles were glial. A different distribution of Met-immunoreactive profiles was observed in layer V of somatosensory cortex: Met-labeled spines were rare and a smaller proportion of glial profiles expressed Met. Strikingly, Met-immunoreactive presynaptic profiles predominated over postsynaptic profiles as early as P7. PLA analysis of neurons in vitro and biochemical analysis of tissue subsynaptic fractions confirmed the localization of Met in specific synaptic subcompartments. The study demonstrates that Met is enriched at synapses during development and its activation may modulate synapse formation and stability through both pre- and post-synaptic mechanisms.

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Estrogen-regulated synaptogenesis in the hippocampus: Sexual dimorphism in vivo but not in vitro

Cited by 96 publications

References 30 publications

Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus

Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus

Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus

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