Neuron-derived estrogen regulates synaptic plasticity and memory

Yujiao Lu, Gangadhara R. Sareddy, Jing Wang, Ruimin Wang, Yong Li, Yan Dong, Quanguang Zhang, Jinyou Liu, Jason C. O’Connor, Jianhua Xu, Ratna K. Vadlamudi, Darrell W Brann

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70-80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenous in vivo E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, in vitro studies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatment in vitro. Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain.

Original languageEnglish (US)
Pages (from-to)2792-2809
Number of pages18
JournalJournal of Neuroscience
Volume39
Issue number15
DOIs
StatePublished - Apr 10 2019

Fingerprint

Neuronal Plasticity
Aromatase
Prosencephalon
Estrogens
Neurons
Knockout Mice
Long-Term Potentiation
Brain
Brain-Derived Neurotrophic Factor
Mitogen-Activated Protein Kinase Kinases
Cerebral Cortex
Cognition
Androgens
Fear
Estradiol
Hippocampus
Spine
Phosphotransferases
Anxiety

Keywords

  • Aromatase
  • Cerebral cortex
  • Cognition
  • Estrogen
  • Hippocampus
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neuron-derived estrogen regulates synaptic plasticity and memory. / Lu, Yujiao; Sareddy, Gangadhara R.; Wang, Jing; Wang, Ruimin; Li, Yong; Dong, Yan; Zhang, Quanguang; Liu, Jinyou; O’Connor, Jason C.; Xu, Jianhua; Vadlamudi, Ratna K.; Brann, Darrell W.

In: Journal of Neuroscience, Vol. 39, No. 15, 10.04.2019, p. 2792-2809.

Research output: Contribution to journalArticle

Lu, Y, Sareddy, GR, Wang, J, Wang, R, Li, Y, Dong, Y, Zhang, Q, Liu, J, O’Connor, JC, Xu, J, Vadlamudi, RK & Brann, DW 2019, 'Neuron-derived estrogen regulates synaptic plasticity and memory', Journal of Neuroscience, vol. 39, no. 15, pp. 2792-2809. https://doi.org/10.1523/JNEUROSCI.1970-18.2019
Lu, Yujiao ; Sareddy, Gangadhara R. ; Wang, Jing ; Wang, Ruimin ; Li, Yong ; Dong, Yan ; Zhang, Quanguang ; Liu, Jinyou ; O’Connor, Jason C. ; Xu, Jianhua ; Vadlamudi, Ratna K. ; Brann, Darrell W. / Neuron-derived estrogen regulates synaptic plasticity and memory. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 15. pp. 2792-2809.
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