Schober A, Wolf N, Huber K, Hertel R, Krieglstein K, Minichiello L, Kahane N, Widenfalk J, Kalcheim C, Olson L, Klein R, Lewin G R, Unsicker K
Department of Anatomy and Cell Biology III, University of Heidelberg, D-69120 Heidelberg, Germany.
J Neurosci. 1998 Sep 15;18(18):7272-84. doi: 10.1523/JNEUROSCI.18-18-07272.1998.
The adrenal medulla receives its major presynaptic input from sympathetic preganglionic neurons that are located in the intermediolateral (IML) column of the thoracic spinal cord. The neurotrophic factor concept would predict that these IML neurons receive trophic support from chromaffin cells in the adrenal medulla. We show here that adrenal chromaffin cells in the adult rat store neurotrophin (NT)-4, but do not synthesize or store detectable levels of BDNF or NT-3, respectively. Preganglionic neurons to the adrenal medulla identified by retrograde tracing with fast blue or Fluoro-Gold (FG) express TrkB mRNA. After unilateral destruction of the adrenal medulla, 24% of IML neurons, i.e., all neurons that are preganglionic to the adrenal medulla in spinal cord segments T7-T10, disappear. Administration of NT-4 in gelfoams (6 microgram) implanted into the medullectomized adrenal gland rescued all preganglionic neurons as evidenced by their presence after 4 weeks. NT-3 and cytochrome C were not effective. The action of NT-4 is accompanied by massive sprouting of axons in the vicinity of the NT-4 source as monitored by staining for acetylcholinesterase and synaptophysin immunoreactivity, suggesting that NT-4 may enlarge the terminal field of preganglionic nerves and enhance their access to trophic factors. Analysis of TrkB-deficient mice revealed degenerative changes in axon terminals on chromaffin cells. Furthermore, numbers of FG-labeled IML neurons in spinal cord segments T7-T10 of NT-4-deficient adult mice were significantly reduced. These data are consistent with the notion that NT-4 from chromaffin cells operates through TrkB receptors to regulate development and maintenance of the preganglionic innervation of the adrenal medulla.
肾上腺髓质主要接受来自位于胸段脊髓中间外侧（IML）柱的交感神经节前神经元的突触前输入。神经营养因子概念预测，这些IML神经元接受来自肾上腺髓质嗜铬细胞的营养支持。我们在此表明，成年大鼠肾上腺嗜铬细胞储存神经营养蛋白（NT）-4，但不分别合成或储存可检测水平的脑源性神经营养因子（BDNF）或NT-3。用快蓝或荧光金（FG）逆行追踪鉴定的肾上腺髓质节前神经元表达TrkB mRNA。单侧破坏肾上腺髓质后，24%的IML神经元，即脊髓T7-T10节段中所有肾上腺髓质的节前神经元消失。将NT-4（6微克）注入植入去肾上腺的明胶海绵中，4周后可见所有节前神经元，证明其可挽救这些神经元。NT-3和细胞色素C无效。通过乙酰胆碱酯酶染色和突触素免疫反应性监测发现，NT-4的作用伴随着NT-4源附近轴突的大量发芽，这表明NT-4可能扩大节前神经的终末场并增强它们对营养因子的获取。对TrkB缺陷小鼠分析显示，嗜铬细胞上的轴突终末出现退行性变化。此外，NT-4缺陷成年小鼠脊髓T7-T10节段中FG标记的IML神经元数量显著减少。这些数据与以下观点一致，即嗜铬细胞产生的NT-4通过TrkB受体发挥作用，以调节肾上腺髓质节前神经支配的发育和维持。
