Synaptic Aromatase; a Novel Form of Estrogen Delivery

描述（由申请人提供）：通过内分泌途径以及大脑自身内的旁分泌和自分泌机制向神经途径提供类固醇。这些传递方式是类固醇（如雌激素）对脊椎动物大脑和行为（包括鸣禽）产生重大影响的基础。使用一种新的抗体，我们已经发现，雌激素可以提供给特定的端脑神经元通过突触神经支配的斑胸草雀（Taeniopygia guttata）。这种“突触分泌”机制涉及芳香化酶向远离其来源的突触末梢的转运。这种作用结合了内分泌活动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，在突触后密度的离子载体和雌激素受体的芳香化酶活性的快速调制强烈表明，突触前的芳香化是功能性的。在斑胸草雀和金丝雀（Serinus canarius），我们将确认突触芳香化酶的表达，使用放射酶测定和免疫电子显微镜。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，我们将建立突触芳香化酶与雌激素和雄激素受体的相互作用，使用双标记共聚焦和电子显微镜。目前，虽然突触芳香化酶已被记录在几个物种，包括人类，没有什么是知道它的调节和功能。这些研究将描述耦合电和激素信号的机制，可能揭示神经内分泌功能的基本和新特征。

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.