Nerve Growth Factor Effects on CNS Cholinergic Neurons In Vivo

  • S. Varon
  • F. H. Gage
  • T. Hagg
  • H. L. Vahlsing
  • M. Manthorpe
Conference paper
Part of the NATO ASI Series book series (volume 22)


Levi-Montalcini’s discovery of Nerve Growth Factor (NGF) some 40 years ago has inspired dramatic changes in our perception of the nervous system as a highly regulated cell society. The concept that specific proteins (designated as neuronotrophic factors, or NTFs) are required for survival, growth and function of selected neuronal populations in the peripheral nervous system (PNS) during its development is being increasingly extended to the central nervous system (CNS) as well as to adult neurons in both PNS and CNS (Varon et al 1984; 1987a-d). If adult CNS neurons do depend throughout life on appropriately supplied NTFs, then it is possible to speculate that i) conditions leading to a deficient or defective NTF supply may be responsible for certain involutive or pathologic situations (Varon, 1975; Appel 1981), and/or ii) administration of exogenous NTFs could protect CNS neurons against such a deficit or alleviate their functional impairments.


Nerve Growth Factor Cholinergic Neuron Cresyl Violet Medial Septum Septal Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literature References

  1. Appel SH (1981) A unifying hypothesis for the cause of Amyotrophic Lateral Sclerosis, Parkinsonism, and Alzheimer disease. Ann Neurol 10:499–505PubMedCrossRefGoogle Scholar
  2. Armstrong EM, Terry RD, DeTeresa RM, Bruce G, Hersh LB, Gage FH (1987) Response of septal cholinergic neurons to axotomy. J Comp Neurol, submittedGoogle Scholar
  3. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417PubMedCrossRefGoogle Scholar
  4. Bjorklund A, Stenevi U (1979) Regeneration of monoaminergic and cholinergicneurons in the mammalian central nervous system. Physiol Rev 59:62–100PubMedGoogle Scholar
  5. Collins F (1978) Induction of neuritic outgrowth by a conditioned-medium factor bound to the culture substratum. Proc Natl Acad Sci USA 75:5210–5213PubMedCrossRefGoogle Scholar
  6. Cotman CW (ed) (1978) Neuronal plasticity. Raven Press, New YorkGoogle Scholar
  7. Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science 219:1184–1190PubMedCrossRefGoogle Scholar
  8. Davis GE, Blaker SN, Engvall E, Varon S, Manthorpe M, Gage FH (1987a) Human amnion membrane serves as a substratum for growing axons in vitro and in vivo. Science, in pressGoogle Scholar
  9. Davis GE, Engvall E, Varon S, Manthorpe M (1987b) Human amnion membrane as a substratum for cultured peripheral and central nervous system neurons. Dev Brain Res, in pressGoogle Scholar
  10. Davis GE, Klier, FG, Engvall E, Cornbrooks C, Varon S, Manthorpe M (1987c) Association of laminin with heparan and chondroitin sulfate-bearing proteoglycans in neurite-promoting complexes from rat Schwannoma cells. Neurochem Res, in pressGoogle Scholar
  11. Gage FH, Bjorklund A, Stenevi U (1984a) Denervation releases a neuronal survival factor in adult rat hippocampus. Nature (London) 308:637–639CrossRefGoogle Scholar
  12. Gage FH, Bjorklund A, Stenevi U, Dunnett SB, Kelly PAT (1984b) Intrahippocampal septal grafts ameliorate learning impairment in aged rats. Science 225:533–536PubMedCrossRefGoogle Scholar
  13. Gage FH, Kelly PAT, Bjorklund A (1984c) Regional changes in brain glucose metabolism reflect cognitive impairments in aged rats. J Neurosci 4(11): 2856–2866PubMedGoogle Scholar
  14. Gage FH, Wictorin K, Fischer W, Williams LR, Varon S, Bjorklund A (1986a) Retrograde cell changes in medial septum and diagonal band following fimbria-fornix transection: quantitative temporal analysis. Neurosci 19:241–255CrossRefGoogle Scholar
  15. Gage FH, Wictorin K, Fisher W, Williams LR, Varon S, Bjorklund A (1986b) Chronic intracerebral infusion of Nerve Growth Factor (NGF) improves memory performance in cognitively impaired aged rats. Soc Neurosci Abstr 12:1580Google Scholar
  16. Hefti F (1986) Nerve Growth Factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6:2155–2162PubMedGoogle Scholar
  17. Hefti F, Dravid A, Hartikka J (1984) Chronic intraventricular injections of Nerve Growth Factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal lesions. Brain Res 293:305–311PubMedCrossRefGoogle Scholar
  18. Hefti F, Hartikka JJ, Eckenstein F, Gnahn H, Heumann R, Schwab M (1985) Nerve Growth Factor increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons. Neuroscience 14:55–68PubMedCrossRefGoogle Scholar
  19. Hepler DJ, Wenk GL, Cribbs BL, Olton OS, Coyle JT (1985) Memory impairments following basal forebrain lesions. Brain Res 346:8–14PubMedCrossRefGoogle Scholar
  20. Korsching S, Auburger G, Heumann R, Scott J, 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 4:1389–1393PubMedGoogle Scholar
  21. Korsching S, Heumann R, Thoenen H, Hefti F (1986) Cholinergic denervation of the rat hippocampus by fimbrial transection leads to a transient accumulation of nerve growth factor (NGF) without change in mRNA NGF content. Neurosci Lett 66:175–180PubMedCrossRefGoogle Scholar
  22. Kromer LF (1987) Nerve Growth Factor treatment after brain injury prevents neuronal death. Science 235:214–216PubMedCrossRefGoogle Scholar
  23. Kromer LF, Bjorklund A, Stenevi U (1981) Regeneration of the septohippocampal pathways in adult rats is promoted by utilizing embryonic hippocampal implants as bridges. Brain Res 210:173–200PubMedCrossRefGoogle Scholar
  24. Lander AD, Fujii DK, Reichardt LF (1985) Laminin is associated with the “neurite outgrowth promoting factors” found in conditioned media. Proc Natl Acad Sci USA 82: 2183–2189PubMedCrossRefGoogle Scholar
  25. Longo FM, Hayman EG, Davis GE, Ruoslahti E, Engvall E, Manthorpe M, Varon S (1981) Neurite promoting factors and extracellular matrix components accumulating in vivo within nerve regeneration chambers. Brain Res 309:105–117PubMedCrossRefGoogle Scholar
  26. Manthorpe M, Engvall E, Ruoslahti E, Longo FM, Davis GE, Varon S (1983) Laminin promotes neuritic regeneration from cultured peripheral and central neurons. J Cell Biol 97:1882–1890PubMedCrossRefGoogle Scholar
  27. Rudge JS, Manthorpe M, Varon S (1985) The output of neuronotrophic and neurite-promoting agents from rat brain astroglial cells: A microculture method for screening potentisl regulstory molecules. Dev Brsin Res 19:161–172CrossRefGoogle Scholar
  28. Taniuchi M, Schweizer JB, Johnson EM (1986) Nerve growth factor receptor molecules in rat brain. Proc Natl Acad Sci USA 83:1950–1951PubMedCrossRefGoogle Scholar
  29. Terry RD, Davies P (1980) Dementia of the Alzheimer type. Annu Rev Neurosci 3:77–95PubMedCrossRefGoogle Scholar
  30. Varon S (1975) In vitro approaches to the study of neural tissue aging. In: Maletta G (ed), Survey of the Aging Nervous System. DHEW Pub (NIH) 74–296, pp 59–76Google Scholar
  31. Varon S, Manthorpe M, Williams LR (1981) Neuronotrophic and neurite promoting factors and their clinical potentials. Dev Neuroscience 6(2):73–100CrossRefGoogle Scholar
  32. Varon S, Manthorpe M, Davis GE, Williams LR, Skaper SD (1987a) Growth Factors. In: Waxman SG (ed), Physiological Basis for Functional Recovery in Neurological Disease. Raven Press, in pressGoogle Scholar
  33. Varon S, Manthorpe M, Williams LR, Gage FH (1987b) Neuronotrophic factors and their involvements in the adult CNS. In: Terry R, Klier FG, Cornbrooks C (eds), Aging and the Brain. Raven Press, New York, in pressGoogle Scholar
  34. Varon S, Williams LR, Gage FH (1987c) Exogenous administration of neuronotrophic factors in vivo protects central nervous system neurons against axotomy induced degeneration. In: Seil FJ, Herbert E, Carlson BM (eds), Neural Regeneration. Progress in Brain Research, Vol 71, Elsevier, pp 191–201CrossRefGoogle Scholar
  35. Varon S, Williams LR, Gage FH (1987d) In vivo protection by an exogenous neuronotrophic factor against neuronal death in adult rat CNS. In: Masland R, Portera-Sanchez A, Toffano G (eds), Neuroplasticity: A New Therapeutical Tool in CNS Pathology. FIDIA Research Series, Liviana Press, Padova, Italy, in pressGoogle Scholar
  36. Williams LR, Vahlsing HL, Lindamood T, Varon S, Gage FH, Manthorpe M (1987) A small gauge cannula device for continuous infusion of exogenous agents into the brain. Exp Neurol 95:743–754PubMedCrossRefGoogle Scholar
  37. Williams LR, Varon S, Peterson G, Wictorin K, Fischer W, Bjorklund A, Gage FH (1986) Continuous infusion of Nerve Growth Factor prevents basal forebrain neuronal death after fimbria-fornix transection. Proc Natl Acad Sci 83:9231–9235PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • S. Varon
    • 1
  • F. H. Gage
    • 2
  • T. Hagg
    • 1
  • H. L. Vahlsing
    • 1
  • M. Manthorpe
    • 1
  1. 1.University of California San DiegoLa JollaUSA
  2. 2.Departments of Biology and NeurosciencesUniversity of California San DiegoLa JollaUSA

Personalised recommendations