Effect Of Brain-specific Overexpression Of Estrogen Synthetase On Cognitive Function

Learning and memory, the advanced function of brain, is based on hundreds of billions of neurons in the human brain. Synapses formed by two adjacent neurons mediate the transmission of information between neurons. They allow electrical or chemical signals to pass from one neuron to another, and are the basis for neurons to perform various functions. The morphology and functions of synapses can be changed unpon various external stimuli, which is so-called synaptic plasticity.Synaptic plasticity allows synaptic strength to be dynamically altered between neurons, therefore, affects the information transmission between them. Thus,learning and memory relies on synaptic plasticity that the ability to change the strength of synaptic connections between neurons.In addition to neurons, astrocytes are important cells in the brain. They modulate learning and memory by maintaining brain hemostasis, supporting neurons,and repairing neurons when they are damaged. Astrocytes also regulate the formation of new memories by mediating synaptic plasticity and synaptogenesis.Estrogen also plays an important role in learning and memory. Previous studies have demonstrated that estrogen can improve learning and memory and reduce the risk of dementia. Moreover, suppression of the synthesis of endogenous estrogen in women leads to cognitive impairment. Therefore, we hypothesized that increasing estrogen in the brain would enhance learning and memory. Because in brain, both neurons and astrocytes are able to produce estrogen, we will further investigate estrogen produced by which kind of cells would enhance the cognitive functions of mice.To answer these two questions, we first generated Thy1-Ar mice in which aromatase, the estrogen synthetase, specifically overexpresses in neurons, and hGFAP-Ar mice, in which aromatase overexpresses in astrocytes. From western blot results, we found significantly increased expression of aromatase in the brain of Thyl-Ar and hGFAP-Ar mice compared to wild type littermates. To study whether the learning and memory ability will improve in estrogen overexpressed mice .In barns behavioral test, we found that the time it took the 13-15 months old Thy1-Ar and hGFAP-Ar mice to find the target hole was significantly less than the age-matched wild type mice. This suggested that 13-15 months old Thyl-Ar and hGFAP-Ar mice showed significant improved learning and memory compared to wild type mice. And 3-5 months old hGFAP-Ar mice showed significant improved learning and memory compared to wild type mice, Thyl-Ar mice showed significant improved learning and memory compared to wild type mice. In the end, we also explored the possible mechanism of estrogen enhanced the ability of learning and memory through the patch clamp technique. We found that hGFAP-Ar mice significant enhanced the excitatory postsynaptic current compared to wild type mice,which was consistent with our behavioral data, indicating that hGFAP-Ar mice were better at learning and memory than wild-type mice. This suggests that the estrogen produced by astrocytes may enhance learning and memory by enhancing the excitatory synaptic transmission capacity. Interestingly, we found that female Thyl-Ar mice showed enhanced learning and memory ability compared to wild type mice, although the excitatory postsynaptic current did not change. This suggests that the mechanisms that estrogen produced by neurons enhances the learning and memory are different from astrocytes.The successful generation of these two transgenic mice provides propriated mice models for studying the role of estrogen in learning and memory. The studies in this thesis has preliminarily demonstrated that overexpression of estrogen synthetase in the brain, no matter in neurons or astrocytes, would improved cognitive functions, although the mechanisms might be different. This observation would potentially provide a therapeutical target for the dementia related to estrogen deficiency. Our findings could also be useful in research of related diseases, such as Alzheimer's disease.