Synaptic Aromatase; a Novel Form of Estrogen Delivery

描述(由申请人提供)：向神经通路提供类固醇是通过内分泌途径实现的，但也是通过大脑本身的旁分泌和自分泌机制实现的。这些给药方式是雌激素等类固醇对脊椎动物的大脑和行为(包括鸣禽)产生重大影响的基础。使用一种新的抗体，我们发现雌激素可以通过斑雀的突触神经支配向特定的端脑神经元提供雌激素。这种“突触分泌”机制涉及芳香酶向远离其来源的突触终末的运输。这种作用结合了内分泌事件的长程特性和轴突神经支配的靶向性。突触前芳构化可以显著改变突触间隙中的类固醇环境，从而改变突触功能。最近的研究结果表明，在突触后的密度下，离子载体和雌激素受体对芳香酶活性的快速调节强烈地表明，突触前的芳构化是有功能的。在斑马雀和金丝雀(Serinus Canarius)中，我们将使用放射酶分析和免疫电子显微镜来证实突触芳香酶的表达。其次，我们将测试突触体和微体芳香化酶的差异调节，以及突触芳构化与歌唱行为的关联。最后，我们将利用双标记共聚焦和电子显微镜建立突触芳香酶与雌激素和雄激素受体的相互作用。目前，虽然已经在包括人类在内的几个物种中发现了突触芳香酶，但对其调节和功能知之甚少。这些研究将描述一种耦合电和激素信号的机制，可能揭示神经内分泌功能的一个基本和新颖的特征。

DESCRIPTION (Provided by applicant): Steroid provision to neural pathways is achieved via endocrine pathways, but also paracrine and autocrine mechanisms within the brain itself. These modes of delivery underlie the considerable influence of steroids like estrogen on vertebrate brain and behavior, including that of songbirds. Using a novel antibody, we have discovered that estrogen can be provided to specific telencephalic neurons via synaptic innervation in the zebra finch (Taeniopygia guttata). This "synaptocrine" mechanism involves the transport of aromatase to synaptic terminals far from their source. This action combines the long-range characteristic of endocrine events with the targeted specificity of axonal innervation. Presynaptic aromatization could dramatically alter the steroidal milieu in the synaptic cleft, thus altering synaptic function. Recent findings that show the rapid modulation of aromatase activity by ionophores and estrogen receptor at post-synaptic densities strongly suggest that presynaptic aromatization is functional. In zebra finches and canaries (Serinus canarius), we will confirm the expression of synaptic aromatase using radioenzymatic assays and immuno-electron microscopy. Second, we will test the differential regulation of synaptosomal and microsomal aromatase, and the association of synaptic aromatization with singing behavior. Finally, we will establish the interaction of synaptic aromatase with estrogen- and androgen receptors using double-label confocal and electron microscopy. Presently, although synaptic aromatase has been documented in several species, including humans, nothing is known about its regulation and function. These studies will describe a mechanism that couples electrical and hormonal signaling, possibly revealing a fundamental and novel characteristic of neuroendocrine function.