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The Journal of Neuroscience, September 15, 1998, 18(18):7272-7284

TrkB and Neurotrophin-4 Are Important for Development and Maintenance of Sympathetic Preganglionic Neurons Innervating the Adrenal Medulla

Andreas Schober¹, Nicole Wolf¹, Katrin Huber¹, Richard Hertel¹, Kerstin Krieglstein¹, Liliana Minichiello³, Nitza Kahane², Johan Widenfalk⁴, Chaya Kalcheim², Lars Olson⁴, Rüdiger Klein³, Gary R. Lewin⁵, and Klaus Unsicker¹

¹ Department of Anatomy and Cell Biology III, University of Heidelberg, D-69120 Heidelberg, Germany, ² Department of Anatomy and Embryology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel, ³ European Molecular Biology Laboratory, Developmental Biology Program, D-69012 Heidelberg, Germany, ⁴ Department of Neuroscience, Karolinska Institute, S-17177 Stockholm, Sweden, and ⁵ Max Delbrück Institute for Molecular Medicine, Berlin-Buch, D-13122, Germany

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 µg) 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.

Key words: adrenal chromaffin cells; neurotrophins; neurotrophin receptors; spinal cord neurons; knock-out mice; NT-4

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187272-13$05.00/0

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