Student Theses and Dissertations

Date of Award

2009

Document Type

Thesis

RU Laboratory

McEwen Laboratory

Keywords

estradiol, PI3 kinase/Akt, brain-derived neurotrophic factor (BDNF), hippocampal function

Abstract

At several points in a woman’s life, changes in circulating estradiol are associated with disturbances in mood and cognitive function. To determine the biological basis of these behavioral changes, researchers have concentrated on the hippocampal formation, a medial temporal lobe structure involved in the regulation of mood and cognition in humans. It is now clear that estradiol increases the substrates of hippocampal synaptic plasticity, including dendritic spine density, synapse density, and synaptic protein expression. In some cases, these changes are associated with alterations in mood and hippocampal-dependent learning and memory. The upstream mediators of these estradiol effects remain unknown, but likely candidates may be inferred from known regulators of hippocampal synaptic plasticity and estradiol effects in other tissues. This thesis explored estradiol activation of two of these candidates, PI3 kinase/Akt and brain-derived neurotrophic factor (BDNF), in the dorsal hippocampus of female mice. In naturally cycling and ovariectomized female mice, estradiol increased hippocampal Akt and BDNF signaling as determined by immunocytochemistry and in situ hybridization. These effects were associated with changes in synaptic protein expression, and required specific estrogen receptor isoforms, as demonstrated using estrogen receptor knockout mice. Immuno-electron microscopy revealed that estradiol specifically increased signaling through presynaptic TrkB receptors in Schaffer collateral and mossy fiber axons. Estradiol effects on Akt signaling were associated with changes in spatial memory ability, and were profoundly altered in mice expressing the BDNF variant Val66Met. This study therefore identifies Akt and BDNF signaling as important upstream pathways in the control of hippocampal function by ovarian steroids in vivo. Circulating estradiol activates Akt rapidly through a BDNF-dependent mechanism, and increases expression of BDNF more slowly, leading to increased activation of the BDNF receptor TrkB. After activation, Akt and TrkB may participate in estradiol regulation of spine synapse density and hippocampal cell excitability. Future studies should aim to understand the specific role of Akt and BDNF in estradiol modulation of hippocampal function and behavior.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/515

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