The Women's Health Initiative (WHI) reported in 2003-2004 that hormone replacement therapy, either progesterone and estrogen in combination or estrogen alone, provided no cardiovascular or cognitive benefit in postmenopausal women. These conclusions lead millions of women to withdraw from hormone replacement therapy. However, clear benefits observed in epidemiological studies have initiated a critical reevaluation of the WHI study. Potential conflicts include the use of equine conjugated hormones, the duration of hormone deficiency, and the advanced age of the subjects. It is becoming increasingly obvious that there is a """"""""window of opportunity"""""""" in which hormone replacement is beneficial for maintaining both cardiovascular and cognitive health. Unfortunately, our understanding of why E2 replacement may or may not rescue cognitive deficit is hindered by insufficient mechanistic information at the cellular level regarding how E2 modulates synaptic function. Thus, the discrepancy in the clinical data will only be resolved by further investigation into the basic mechanisms through which E2 acts. Because all women undergo menopause and spend nearly 1/3 of their life in this state, intensive research effort must be dedicated to obtaining new knowledge that will provide insight for interventions to sustain mental and cognitive health. At hippocampal CA3-CA1 synapses, estradiol (E2) increases spine density, NMDAR transmission, and LTP5-8, mechanisms believed to underlie the enhanced memory. However, it remains unknown whether there is a functional relationship between the increased spine density and LTP. This is important because in aged animals, E2 increases NMDAR expression but not spine density, which may explain the age related decrease in cognitive benefit of E2 replacement therapy. On the other hand, aged animals may be able to increase plasticity without the growth of new synapse. It is also not known whether the cortical input onto CA1 cells from the entorhinal cortex is modulated by E2 similarly to CA3 Schaffer collateral synapses. This is critical to know because these synapses drive CA1 cells during spatial exploration and estradiol increases spatial memory. It is known that E2 requires cholinergic innervation to enhance memory, but is it not known whether the same is true for the increase in synaptic function. Because E2 protects cholinergic cells from degeneration, loss of E2 in menopause could lead to increased cholinergic cell death. This is significant because post menopausal women are at greater risk of developing Alzheimer's disease than men and E2 replacement decreases this risk. Therefore insufficient cholinergic transmission would limit the ability of E2 to cause cognitive benefit. Finally, no study has investigated the impact of prolonged hormone loss on the ability of E2 to induce changes in synaptic function. Only one study has investigated potential alterations in NMDAR mRNA levels, but no significant results were observed. This is of high clinical importance because determining the window of opportunity and how this relates to chronological age is absolutely essential to further our understanding of the effectiveness of hormone replacement therapy. In this proposal, we will use extracellular dendritic field potential and whole-cell patch clamp recording techniques in area CA1 of acute slices from young adult, middle aged and aged ovariectomized (OVX) female rats treated with estradiol or vehicle to pursue the following Specific Aims:
AIM 1 will test the hypothesis that E2 increases the magnitude of LTP by increasing the density of silent synapses which express NMDARs containing NR2B subunits;
AIM 2 will test the hypothesis that E2 mediated effects on spine density and synaptic function are not limited to the Schaffer collateral pathway but also include synapses between the entorhinal cortex and the distal dendrites of CA1 pyramidal cells;
AIM3 will test the hypothesis that cholinergic denervation will prevent the E2 induced increase in spine density, NMDAR transmission, and LTP magnitude but that sympathetic sprouting from the superior cervical ganglia will rescue these deficits;
AIM 4 will test the hypothesis that prolonged hormone loss combined with normal aging prevents the ability of E2 replacement to induce morphological and functional changes at CA3-CA1 synapses.

Public Health Relevance

a normal consequence of aging in women is the loss of estrogen due to menopause. This hormone loss, which is linked to memory deficits in post-menopausal women, is one of the clearest examples of a non-disease age-related loss in memory. Detailed knowledge of the precise alterations in hippocampus that are induced by estrogen is needed to unravel the role of this hormone in normal memory and how its loss in aging results in memory deficits. In order to understand the relationship be estrogen loss and hippocampal cognitive deficits in aging, it is necessary to first obtain a precise picture of how estrogen alters function in hippocampus in young adults. In this study we will use ovariectomized female rats treated with estrogen to determine how this hormone manipulates activity of excitatory synapses in hippocampus, whose function is required for normal memory. We will also pursue how the effects of estrogen are altered in aging and by the degeneration of cholinergic neurons which are a critical player in estrogen's ability to modify hippocampal function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Desmond, Nancy L
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University of Alabama Birmingham
Schools of Medicine
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Smith, Caroline C; Smith, Lindsey A; Bredemann, Teruko M et al. (2016) 17? estradiol recruits GluN2B-containing NMDARs and ERK during induction of long-term potentiation at temporoammonic-CA1 synapses. Hippocampus 26:110-7
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