Lustig R H, Hua P, Wilson M C, Federoff H J
Department of Pediatrics, University of Wisconsin, Madison 53792.
Brain Res Mol Brain Res. 1993 Oct;20(1-2):101-10. doi: 10.1016/0169-328x(93)90114-5.
Sex hormones influence neurite outgrowth and synaptogenesis in certain hormone-dependent areas of the rat brain during neonatal development. These alterations are thought to mediate changes in brain structure and function between the sexes. Growth-associated protein 43 kDa (GAP-43) gene expression is estrogen-regulated in the adult ventromedial hypothalamus (VMH) and sexually dimorphic (M:F = 1.8:1) in adult cortex (CTX). Such effects intimate hormonal regulation of synaptic plasticity. To investigate the nature of these dimorphisms, the present study examined the ontogeny of expression of mRNAs encoding 3 neural-specific proteins: GAP-43, SCG10, and synaptosomal-associated protein 25 kDa (SNAP-25); and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in the VMH and CTX; and also the effects of altering the neonatal sex hormonal milieu on the development of these adult dimorphisms. Levels of specific mRNAs in VMH and CTX were quantitated by slot-blot hybridization in rats of both sexes at different postnatal ages. To determine the involvement of neonatal sex hormones on the levels of these mRNAs, male neonatal rat pups were treated with an estrogen receptor antagonist or an aromatase inhibitor, and neonatal female pups were treated with testosterone or estrogen prior to slot-blot evaluations in adulthood. In VMH, GAP-43 mRNA levels were high on days P1 and P4 with a 3-fold decrease by day P23; in CTX, GAP-43 mRNA first increased by day P11, then fell to baseline by day P23. In VMH, SCG10 mRNA showed only small increases with time; but in CTX, there was a 5-fold drop from days P4 to P23. In VMH, SNAP-25 mRNA was low and changed only slightly; but in CTX there was a 5-fold increase between days P4 and P60. At birth, there was no sex dimorphism in either VMH or CTX, but the levels of all 3 neural-specific mRNAs were sexually dimorphic in adult CTX (M:F = 1.76 for GAP-43, 1.46 for SCG10, 1.44 for SNAP-25). GAPDH mRNA levels were regulated developmentally in VMH and CTX, but there was no sex dimorphism in either area. In male rats who received either an estrogen antagonist or aromatase inhibitor at birth, the CTX GAP-43 and SNAP-25 mRNA levels fell by 30%, to levels similar to untreated females. Conversely, in female rats, neonatal treatment with either testosterone or estrogen increased GAP-43 and SNAP-25 mRNA levels by about 30%, to levels similar to the untreated adult male. SCG10 levels did not demonstrate neonatal hormonal dependence.(ABSTRACT TRUNCATED AT 400 WORDS)
在新生大鼠发育过程中，性激素会影响大鼠脑内某些激素依赖区域的神经突生长和突触形成。这些改变被认为介导了两性之间脑结构和功能的变化。在成年腹内侧下丘脑（VMH）中，43 kDa生长相关蛋白（GAP - 43）基因表达受雌激素调节，在成年皮质（CTX）中具有性别二态性（雄∶雌 = 1.8∶1）。这些效应表明激素对突触可塑性具有调节作用。为了研究这些二态性的本质，本研究检测了编码3种神经特异性蛋白的mRNA的表达个体发生过程，这3种蛋白分别为：GAP - 43、SCG10和25 kDa突触体相关蛋白（SNAP - 25）；以及甘油醛 - 3 - 磷酸脱氢酶（GAPDH）在VMH和CTX中的表达情况；还研究了改变新生期性激素环境对这些成年二态性发育的影响。通过狭缝印迹杂交法对不同出生后年龄的雌雄大鼠VMH和CTX中特定mRNA的水平进行定量。为了确定新生期性激素对这些mRNA水平的影响，在成年期进行狭缝印迹评估之前，对雄性新生大鼠幼崽用雌激素受体拮抗剂或芳香化酶抑制剂进行处理，对新生雌性幼崽用睾酮或雌激素进行处理。在VMH中GAP - 43 mRNA水平在出生后第1天和第4天较高，到出生后第23天下降了3倍；在CTX中，GAP - 43 mRNA在出生后第11天首先升高，然后在出生后第23天降至基线水平。在VMH中，SCG10 mRNA随时间仅有小幅增加；但在CTX中，从出生后第4天到第23天下降了5倍。在VMH中，SNAP - 25 mRNA水平较低且变化不大；但在CTX中，在出生后第4天到第60天之间增加了5倍。出生时，VMH和CTX中均不存在性别二态性，但在成年CTX中所有3种神经特异性mRNA的水平均具有性别二态性（GAP - 43为1.76，SCG10为1.46，SNAP - 25为1.4）。GAPDH mRNA水平在VMH和CTX中受发育调节，但在这两个区域均不存在性别二态性。在出生时接受雌激素拮抗剂或芳香化酶抑制剂处理的雄性大鼠中，CTX中GAP - 43和SNAP - 25 mRNA水平下降了30%，降至与未处理雌性相似的水平。相反，在雌性大鼠中，新生期用睾酮或雌激素处理使GAP - 43和SNAP - 25 mRNA水平增加了约30%，升至与未处理成年雄性相似的水平。SCG10水平未表现出新生期激素依赖性。（摘要截短至400字）
