Estrogen support of Cerebellar Neurotransmission

描述（申请人提供）：小脑对运动的控制至关重要，在认知过程中起着重要作用。在小脑内，雌激素长期以来一直被证明影响突触回路和功能。然而，迄今为止，雌二醇改变小脑输出的机制仍然是个谜。利用最先进的光学成像技术，我们发现雌激素受体信号对于维持连接小脑颗粒细胞和浦肯野神经元的平行纤维突触至关重要。此外，我们发现雌激素受体对平行纤维突触的调节依赖于局部合成的雌二醇。这些影响在雄性和雌性小鼠中都观察到了。由于平行纤维主导着小脑皮层的细胞结构，并且是调节小脑功能的核心元素，我们相信这些数据是我们理解雌激素作用的一个新的基本机制的开始。利用明尼苏达大学两位互补研究者的专业知识和经验，我们的目标是描述这一现象。特异性目的1将确定平行纤维-浦肯野细胞网络内的电活动是否驱动局部神经雌激素的产生。特异性Aim 2将确定雌激素受体(s)负责维持小脑颗粒神经元和浦肯野细胞之间突触神经传递的功效。这一目的还将确定雌激素受体是位于突触前还是突触后。特异性目的3将评估雌激素信号减少对小脑介导的运动行为的功能影响。通过描述雌激素受体支持小脑谷氨酸能神经传递的关键调控机制，我们将揭示神经系统功能的一个迄今未知的方面。此外，这些结果将对使用雌激素受体调节剂有益于健康及其在疾病治疗中的影响具有重要意义。

DESCRIPTION (provided by applicant): The cerebellum is essential for the control of movement and plays an important role in cognitive processes. Within the cerebellum, estrogens have long been demonstrated to affect synaptic circuitry and function. Yet to date, the mechanisms by which estradiol can alter cerebellar output have remained a mystery. Using state-of-the-art optical imaging techniques, we have found estrogen receptor signaling to be essential for the maintenance of the parallel fiber synapses connecting cerebellar granule cells to Purkinje neurons. Further, we have found that estrogen receptor regulation of the parallel fiber synapse to be dependent on locally synthesized estradiol. These effects are observed in both male and female mice. Since parallel fibers dominate the cytoarchitecture of the cerebellar cortex, and are central elements in modulating cerebellar function, we believe these data are the beginnings to our understanding of a new fundamental mechanism of estrogen action. Using the combined expertise and experiences of two complementary investigators at the University of Minnesota, our goal is to characterize this phenomenon. Specific Aim 1 will determine whether electrical activity within the parallel fiber-Purkinje cell network drives local neuroestrogen production. Specific Aim 2 will identify the estrogen receptor(s) responsible for maintaining the efficacy of synaptic neurotransmission between the cerebellar granule neurons and Purkinje cells. This Aim will also determine whether the estrogen receptors are located pre- or postsynaptically. Specific Aim 3 will evaluate the functional impact of diminishing estrogen signaling on cerebellar-mediated locomotor behavior. By characterizing the critical regulatory mechanisms for estrogen receptor support of cerebellar glutamatergic neurotransmission, we will have uncovered a heretofore unknown aspect of nervous system function. In addition, these results will have important implications in the use of estrogen receptor modulators to benefit health and its impact in the treatment of disease. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to characterize the signaling pathway by which locally-synthesized estradiol acts within the cerebellum to support glutamatergic neurotransmission in the parallel fiber network, that is, the connection between cerebellar granule neurons and Purkinje cells. Understanding the requirement of estrogen receptor activation in support of the parallel fiber synapse has important implications not only in cerebellar function, but will impact our perspective regarding the side effects of tamoxifen and aromatase inhibitor therapies. In addition, our work will provide insight into estrogenic support o glutamatergic synaptic function in other brain areas.