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Expression of neuronal-NOS in developing basal forebrain cholinergic neurons: Regulation by NGF

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Abstract

Nerve growth factor (NGF) acts through the receptor tyrosine kinase trkA to serve as a trophic factor for cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band. We have previously shown that the neuronal isoform of nitric oxide synthase (NOS) is selectively expressed in a large fraction of trkA-expressing cholinergic neurons in these brain regions in the adult rat, and that NGF induces the expression of neuronal-NOS in these cells. Herein, we show that: 1) neuronal-NOS is also localized to these neurons in the developing septum; 2) the expression of neuronal-NOS is regulated in the developing medial septal nucleus and vertical limb of the diagonal band; 3) neuronal-NOS regulation parallels that for other markers of basal forebrain cholinergic neuron differentiation, such as cholineacetyltransferase; and 4) NGF infusion in the postnatal period induces robust increases in neuronal-NOS mRNA and in NOS activity in the basal forebrain. Taken together with earlier findings, our results suggest that neuronal-NOS has a role in the differentiation and mature function of septal cholinergic neurons. Through enhancing neuronal-NOS synthesis, endogenous NGF is likely to regulate NO functions in vivo.

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References

  1. Bredt, D. S., and Snyder, S. H. 1994. Nitric oxide: a physiologic messenger molecule. Annu. Rev. Biochem. 63:175–195.

    Article  PubMed  CAS  Google Scholar 

  2. Dawson, T. M., and Snyder, S. H. 1994. Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J. Neurosci. 14(9):5147–5159.

    PubMed  CAS  Google Scholar 

  3. Bredt, D. S., and Snyder, S. H. 1994. Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium. Neuron 13:301–313.

    Article  PubMed  CAS  Google Scholar 

  4. Marletta, M. A. 1994. Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78:927–930.

    Article  PubMed  CAS  Google Scholar 

  5. Garthwaite, J., and Boulton, C. L. 1995. Nitric oxide signalling in the central nervous system. Annu. Rev. Physiol. 57:683–706.

    Article  PubMed  CAS  Google Scholar 

  6. Dinerman, J. L., Dawson, T. M., Schell, M. J., Snowman, A., and Snyder, S. H. 1994. Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: implications for synaptic plasticity. Proc. Natl. Acad. Sci. USA 91:4214–4218.

    Article  PubMed  CAS  Google Scholar 

  7. Huang, P. L., Dawson, T. M., Bredt, D. S., Snyder, S. H., and Fishman, M. C. 1993. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75:1273–1286.

    Article  PubMed  CAS  Google Scholar 

  8. Vincent, S. R. and Hope, B. T. 1992. Neurons that say NO. Trends Neurosci. 15:108–113.

    Article  PubMed  CAS  Google Scholar 

  9. Bohme, G. A., Bon, C., Stutzmann, J.-M., Doble, A., and Blanchard, J.-C. 1991. Possible involvement of nitric oxide in longterm potentiation. Eur. J. Pharm. 199:379–381.

    Article  CAS  Google Scholar 

  10. Schuman, E. M., and Madison, D. V. 1991. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 254:150–1506.

    Article  Google Scholar 

  11. Lev-Ram, V., Makings, L. R., Keitz, P. F, Kao, J. P. Y., and Tsien, R. Y. 1995. Long-term depression in cerebellar purkinje neurons results from coincidence of nitric oxide and depolarization-induced Ca+2 transients. Neuron 15:407–415.

    Article  PubMed  CAS  Google Scholar 

  12. Coyle, J. T., Price, D. L., and DeLong, M. R. 1983. Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190.

    Article  PubMed  CAS  Google Scholar 

  13. Richiardson, R. T., and DeLong, M. R. 1988. A reappraisal of the functions of the nucleus basalis of Meynert. Trends Neurosci. 11: 264–267.

    Article  Google Scholar 

  14. Olton, D., Markowska, A., Voytoko, M. L., Givens, B., Gormon, L., and Wenk, G. 1991. Basal forebrain cholinergic system: a functional analysis. Adv. Exp. Med. Biol. 295:353–372.

    PubMed  CAS  Google Scholar 

  15. Brauer, K., Schober, A., Wolff, J. R., Winkelmann, E., Luppa, H., Luth, H.-J., and Bottcher, H. 1991. Morphology of neurons in the rat basal forebrain nuclei: comparison between NADPH-diaphorase histochemistry and immunohistochemistry of glutamic acid decarboxylase, choline acetyltransferase, somatostatin, and parvalbumin. J. Hirnforsch. 32:1–17.

    PubMed  CAS  Google Scholar 

  16. Kitchener, P. D., and Diamond, J. 1993. Distribution and colocalization of choline acetyltransferase immunoreactivity and NADPH diaphorase reactivity in neurons within the medial septum and diagonal band of brand of Broca in the rat basal forebrain. J. Comp. Neurol. 335:1–15.

    Article  PubMed  CAS  Google Scholar 

  17. Holtzman, D. M., Kilbridge, J., Bredt, D. S., Black, S. M., Li, Y., Clary, D. O., Reichardt, L. F., and Mobley, W. C. 1994. NOS induction by NGF in basal forebrain cholinergic neurons: evidence for regulation of brain NOS by a neurotrophin. Neurobiol. Dis. 1: 51–60.

    Article  PubMed  CAS  Google Scholar 

  18. Thoenen, H. 1995. Neurotrophins and neuronal plasticity. Science 270:593–598.

    Article  PubMed  CAS  Google Scholar 

  19. Korsching, S., Auburger, G., Heumann, R., Scott, J., and Thoenen, H. 1985. Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation. EMBO J. 4:1389–93.

    PubMed  CAS  Google Scholar 

  20. Shelton, D. L., and Reichardt, L. F. 1986. Studies on the expression of beta NGF gene in the central nervous system: Level and regional distribution of NGF mRNA suggest that NGF functions as a trophic factor for several neuronal populations. Proc. Natl. Acad. Sci. USA 83:2714–2718.

    Article  PubMed  CAS  Google Scholar 

  21. Whittemore, S. R., Ebendal, T., Larkfors, L., Olson, L., Seiger, A., Stromberg, I., and Persson, H. 1986. Developmental and regional expression of beta-nerve growth factor messenger RNA and protein in the rat central nervous system. Proc. Natl. Acad. Sci. USA 83:817–821.

    Article  PubMed  CAS  Google Scholar 

  22. Holtzman, D. M., Li, Y., Parada, L. F., Kinsman, S., Chen, C. K., Valletta, J. S., Zhou, J., Long, J., and Mobley, W. C. 1992. p140trk mRNA marks NGF-responsive forebrain neurons: evidence thattrk gene expression is induced by NGF. Neuron 9:465–478.

    Article  PubMed  CAS  Google Scholar 

  23. Holtzman, D. M., Kilbridge, J., Li, Y., Cunningham, E. T., Lenn, N. J., Clary, D. O., Reichardt, L. F., and Mobley, W. C. 1995.TrkA expression in the CNS: evidence for the existence of several novel NGF-responsive CNS neurons. J. Neurosci. 15: 1567–1576.

    PubMed  CAS  Google Scholar 

  24. Steininger, T. L., Wainer, B. H., Klein, R., Barbacid, M., and Palfrey, H. C. 1993. High-affinity nerve growth factor receptor (Trk) immunoreactivity is localized in cholinergic neurons of the basal forebrain and striatum in the adult rat brain. Brain Res. 612: 330–335.

    Article  PubMed  CAS  Google Scholar 

  25. Kaplan, D. R., Hempstead, B. L., Martin-Zanca, D., Chao, M. V., and Parada, L. F. 1991. Thetrk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252(5005): 554–558.

    Article  PubMed  CAS  Google Scholar 

  26. Kaplan, D. R., Martin-Zanca, D., and Parada, L. F. 1991. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350:158–160.

    Article  PubMed  CAS  Google Scholar 

  27. Longo, F. M., Holtzman, D. M., Grimes, M. L., and Mobley, W. C. 1992 Nerve-growth factor: actions in the peripheral and central nervous systems. In “Neurotrophic Factors” (J. Fallon and S. Loughlin, eds). Academic Press, New York, pp. 209–256.

    Google Scholar 

  28. Gnahn, H., Hefti, F., Heumann, R., Schwab, M. E., and Thoenen, H. 1983. NGF-mediated increase of choline acetyltransferase (ChAT) in the neonatal rat forebrain: evidence for a physiological role of NGF in the brain. Dev. Brain Res. 9:42–52.

    Article  Google Scholar 

  29. Mobley, W. C., Rutkowski, J. L., Tennekoon, G. I., Gemski, J., Buchanan, K., and Johnston, M. V. 1986. Nerve growth factor increases choline acetyltransferase activity in developing basal forebrain neurons. Mol. Brain Res. 387(1):53–62.

    Article  CAS  Google Scholar 

  30. Mobley, W. C., Neve, R. L., Prusiner, S. B., and McKinley, M. P. 1988. Nerve growth factor increases mRNA levels for the prion protein and the beta-amyloid protein precursor in developing hamster brain. Proc. Natl. Acad. Sci. U S A 85:9811–9815.

    Article  PubMed  CAS  Google Scholar 

  31. Large, T. H., Bodary, S. C., Clegg, D. O., Weskamp, G., Otten, U., and Reichardt, L. F. 1986. Nerve growth factor gene expression in the developing rat brain. Science 234:352–355.

    Article  PubMed  CAS  Google Scholar 

  32. Vantini, G., Schavo, N., DiMartino, A., Polato, P., Triban, C., Callegaro, L., Toffano, G., and Leon, A. 1989. Evidence for a physiological role for nerve growth factor in the central nervous system of neonatal rats. Neuron 3:267–273.

    Article  PubMed  CAS  Google Scholar 

  33. Li, Y., Holtzman, D. M., Kromer, L. F., Kaplan, D. R., Chua-Couzens, J., Clary, D. O., Knusel, B., and Mobley, W. C. 1995. Coordinate regulation of trkA and ChAT expression in developing rat basal forebrain: evidence that NGF regulates cholinergic differentiation through p140trk. J. Neurosci. 15:2888–2905.

    PubMed  CAS  Google Scholar 

  34. Crowley, C., Spencer, S. D., Nishimura, M. C., Chen, K. S., Pitts, M. S., Armanini, M. P., Ling, L. H., MacMahon, S. B., Shelton, D. L., Levinson, A. D., and Phillips, H. S. 1994. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76:1001–1011.

    Article  PubMed  CAS  Google Scholar 

  35. Smeyne, R. J., Klein, R., Schnapp, A., Long, L. K., Bryant, S., Lewin, A., Lira, S. A., and Barbacid, M. 1994. Severe sensory and sympathetic neuropathies in mice carrying a disrupted TRK/NGF receptor gene. Nature 368:246–249.

    Article  PubMed  CAS  Google Scholar 

  36. Clary, D. O., Weskamp, G., Austin, L. R., and Reichardt, L. F. 1994. TrkA-crosslinking mimics neuronal responses to nerve growth factor. Mol. Biol. Cell 5:549–563.

    PubMed  CAS  Google Scholar 

  37. Mobley, W. C., Rutkowski, J. L., Tennekoon, S. J., Buchanan, K., and Johnston, M. V. 1985. Choline acetyltransferase in striatum of neonatal rats increased by nerve growth factor. Science 229:284–287.

    Article  PubMed  CAS  Google Scholar 

  38. Johnston, M. V., Rutkowski, J. L., Wainer, B. H., Long, J. B., and Mobley, W. C. 1987. NGF effects of developing forebrain cholinergic neurons are regionally specific. Neurochem. Res. 12: 985–994.

    Article  PubMed  CAS  Google Scholar 

  39. Holtzman, D. M., Bayney, R. M., Li, Y., Khosrovi, H., Berger, C. N., Epstein, C. J., and Mobley, W. C. 1992. Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. EMBO J. 11:619–627.

    PubMed  CAS  Google Scholar 

  40. Chirgwin, J. M., Przybyla, A.E., MacDonald, R. J., and Rutter, W. J. 1979. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294–5299.

    Article  PubMed  CAS  Google Scholar 

  41. Bredt, D. S., Glatt, C. E., Hwang, P. M., Fotuhi, M., Dawson, T. M., and Snyder, S. H. 1991. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7: 615–624.

    Article  PubMed  CAS  Google Scholar 

  42. Bowman, L., Rabin, B., and Schlessinger, D. 1981. Multiple ribosomal RNA cleavage pathways in mammalian cells. Nucl. Acids Res. 9:4951–4966.

    PubMed  CAS  Google Scholar 

  43. Dawson, T. M., Bredt, D. S., Fotuhi, M., Hwang, P. M., and Snyder, S. H. 1991. Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Natl. Acad. Sci. USA 88:7797–7801.

    Article  PubMed  CAS  Google Scholar 

  44. Hirsch, D. B., Steiner, J. P., Dawson, T. M., Mammen, A., Hayek, E., and Snyder, S. 1993. Neurotransmitter release mediated by nitric oxide in PC-12 cells and brain synaptosomes. Curr. Biol. 3: 749–754.

    Article  PubMed  CAS  Google Scholar 

  45. Peunova, N., and Enikolopov, G. 1995. Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells. Nature 375:68–73.

    Article  PubMed  CAS  Google Scholar 

  46. Hess, D. T., Patterson, S. I., Smith, D. S., and Pate Skene, J. H. 1993. Neuronal growth cone collapse and inhibition of protein fatty acylation by nitric oxide. Nature 366:562–565.

    Article  PubMed  CAS  Google Scholar 

  47. Farenelli, S. E., Park, D. S., and Greene, L. A. 1996. Nitric oxide delays the death of trophic factor-deprived PC12 cells and sympathetic neurons by a cGMP-mediated mechanism. J Neurosci. in press.

  48. Milner, T. A., Loy, R., and Amaral, D.G. 1983. An anatomical study of the development of the septohippocampal projection in the rat. Dev. Brain Res. 8: 343–371.

    Article  Google Scholar 

  49. Prast, H., and Philippu, A. 1992. Nitric oxide releases acetylcholine in the basal forebrain. Eur. J. Pharmacol. 216:139–140.

    Article  PubMed  CAS  Google Scholar 

  50. Blochl, A., and Thoenen, H. 1995. Characterization of NGF release from hippocampal neurons: evidence for the constitutive and an unconventional sodium-dependent regulated pathway. Eur. J. Neurosci. 7:1220–1228.

    Article  PubMed  CAS  Google Scholar 

  51. Aloe, L. 1987. Intracerebral pretreatment with nerve growth factor prevents irreversible brain lesions in neonatal rats injected with ibotenic acid. Biotechnology 5:1085–1086.

    Article  CAS  Google Scholar 

  52. Holtzman, D. M., Sheldon, R. A., Jaffe, W., Cheng, Y., and Ferriero, D. F. 1996. NGF protects the neonatal brain against hypoxic-ischemic injury. Ann. Neurol. 39:114–122.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Box 8111, 63110, St. Louis, Missouri

    David M. Holtzman

  2. Center for the Study of Nervous System Injury, Washington University School of Medicine, 660 S. Euclid Ave, Box 8111, 63110, St. Louis, Missouri

    David M. Holtzman

  3. Department of Neurology, University of California, San Francisco, 505 Parnassus Ave, Box 0114, 94143, San Francisco, California

    Sandra Lee, Yiwen Li, Jane Chua-Couzens & William C. Mobley

  4. Department of Pediatrics, University of California, San Francisco, 505 Parnassus Ave, Box 0114, 94143, San Francisco, California

    Jane Chua-Couzens

  5. the Neuroscience Program, University of California, San Francisco, 505 Parnassus Ave, Box 0114, 94143, San Francisco, California

    Houhui Xia, David S. Bredt & William C. Mobley

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  1. David M. Holtzman
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  2. Sandra Lee
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Special issue dedicated to Dr. Hans Thoenen.

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Holtzman, D.M., Lee, S., Li, Y. et al. Expression of neuronal-NOS in developing basal forebrain cholinergic neurons: Regulation by NGF. Neurochem Res 21, 861–868 (1996). https://doi.org/10.1007/BF02532310

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