Synaptic Aromatase; a Novel Form of Estrogen Delivery

描述（由申请人提供）：通过内分泌途径向神经通路提供类固醇，但也通过脑内的旁分泌和自分泌机制实现。这些分娩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）产生相当大影响的基础。利用一种新型抗体，我们发现雌性激素可以通过突触神经支配提供给特定的端脑神经元。这种“突触分泌”机制涉及芳香化酶运输到远离其来源的突触末端。这种作用结合了内分泌事件的长程特征和轴突神经支配的靶向特异性。突触前芳构化可显著改变突触间隙中的甾体环境，从而改变突触功能。最近的研究表明，离子载体和雌激素受体在突触后密度下对芳香化酶活性的快速调节强烈表明，突触前芳香化是功能性的。在斑胸草雀和金丝雀（Serinus canarius）中，我们将使用放射酶测定和免疫电镜证实突触芳香酶的表达。其次，我们将测试突触体和微粒体芳香化酶的差异调节，以及突触芳香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化酶与雌激素和雄激素受体的相互作用。目前，虽然突触芳香酶已在包括人类在内的几个物种中被发现，但对其调控和功能尚不清楚。这些研究将描述电和激素信号耦合的机制，可能揭示神经内分泌功能的一个基本和新的特征。

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.