Abstract

Changes in endogenous concentrations of estrogens can influence cognition in humans and animals. Estrogens are thought to affect cognition by modulating synaptic and neuronal function. The hippocampus is important for learning and memory, and estrogens can enhance synaptic transmission in that region. The entorhinal cortex is involved in object recognition, olfaction, and navigation, and provides the hippocampus with most of its cortical sensory and associational inputs. However, the contribution of estrogens to the modulation of entorhinal cortex function is unclear.

The work presented herein used electrophysiological and protein quantification techniques to assess the effects of estrogens in the entorhinal cortex. Electrically evoked postsynaptic field potential recordings (fEPSPs) were used in the first experiments to assess the rapid functional effects of acute 17-estradiol (E2) application on excitatory glutamatergic transmission in the superficial layers of the entorhinal cortex in vitro. Results demonstrated that E2 reversibly facilitates fEPSPs via activation of the membrane-bound G protein-coupled estrogen receptor-1 (GPER1). The second group of experiments further examined the cellular mechanisms of this GPER1-mediated facilitation using whole-cell patch-clamp recordings to measure changes in intracellular postsynaptic currents following E2 exposure. These recordings showed significant reductions in NMDA receptor-mediated excitatory postsynaptic currents and GABAA receptor-mediated inhibitory currents following E2 exposure. This suggests that E2 rapidly suppresses inhibition to facilitate excitatory synaptic transmission.
Diminished estrogenic function following natural or surgical menopause can induce cognitive alterations which may be ameliorated by estrogen supplementation. The loss of estrogens can alter cholinergic function throughout the brain and this may contribute to cognitive alterations. The last group of experiments explored in this thesis tested the effects of prolonged estrogen loss on cholinergic function in the entorhinal cortex. Western blot protein quantification showed significant reductions in acetylcholinesterase and M1 receptor protein following ovariectomy when compared to intact rats, and E2 supplementation following ovariectomy prevented these effects. Application of eserine, an acetylcholinesterase inhibitor, markedly reduced fEPSP amplitudes in all groups, but the reduction observed in ovariectomized rats was significantly reduced compared to intact and E2 supplemented groups. Together, these works provide evidence for the modulation of synaptic function by 17-estradiol in the entorhinal cortex.