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. 1999 Feb;107(Suppl 1):65–69. doi: 10.1289/ehp.99107s165

Morphogenetic roles of acetylcholine.

J M Lauder 1, U B Schambra 1
PMCID: PMC1566361  PMID: 10229708

Abstract

In the adult nervous system, neurotransmitters mediate cellular communication within neuronal circuits. In developing tissues and primitive organisms, neurotransmitters subserve growth regulatory and morphogenetic functions. Accumulated evidence suggests that acetylcholine, (ACh), released from growing axons, regulates growth, differentiation, and plasticity of developing central nervous system neurons. In addition to intrinsic cholinergic neurons, the cerebral cortex and hippocampus receive extensive innervation from cholinergic neurons in the basal forebrain, beginning prenatally and continuing throughout the period of active growth and synaptogenesis. Acute exposure to ethanol in early gestation (which prevents formation of basal forebrain cholinergic neurons) or neonatal lesioning of basal forebrain cholinergic neurons, significantly compromises cortical development and produces persistent impairment of cognitive functions. Neonatal visual deprivation alters developmental expression of muscarinic acetylcholine receptors (mAChR) in visual cortex, whereas local infusion of mAChR antagonists impairs plasticity of visual cortical neurons. These findings raise the possibility that exposure to environmental neurotoxins that affect cholinergic systems may seriously compromise brain development and have long-lasting morphologic, neurochemical, and functional consequences.

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Selected References

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  1. Arimatsu Y., Seto A., Amano T. An atlas of alpha-bungarotoxin binding sites and structures containing acetylcholinesterase in the mouse central nervous system. J Comp Neurol. 1981 Jun 1;198(4):603–631. doi: 10.1002/cne.901980405. [DOI] [PubMed] [Google Scholar]
  2. Armstrong D. M., Bruce G., Hersh L. B., Gage F. H. Development of cholinergic neurons in the septal/diagonal band complex of the rat. Brain Res. 1987 Dec 1;433(2):249–256. doi: 10.1016/0165-3806(87)90028-9. [DOI] [PubMed] [Google Scholar]
  3. Ashkenazi A., Ramachandran J., Capon D. J. Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. Nature. 1989 Jul 13;340(6229):146–150. doi: 10.1038/340146a0. [DOI] [PubMed] [Google Scholar]
  4. Bachman E. S., Berger-Sweeney J., Coyle J. T., Hohmann C. F. Developmental regulation of adult cortical morphology and behavior: an animal model for mental retardation. Int J Dev Neurosci. 1994 Jun;12(4):239–253. doi: 10.1016/0736-5748(94)90071-x. [DOI] [PubMed] [Google Scholar]
  5. Baumgold J. Muscarinic receptor-mediated stimulation of adenylyl cyclase. Trends Pharmacol Sci. 1992 Sep;13(9):339–340. doi: 10.1016/0165-6147(92)90105-f. [DOI] [PubMed] [Google Scholar]
  6. Bear M. F., Singer W. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature. 1986 Mar 13;320(6058):172–176. doi: 10.1038/320172a0. [DOI] [PubMed] [Google Scholar]
  7. Brimijoin S., Koenigsberger C. Cholinesterases in neural development: new findings and toxicologic implications. Environ Health Perspect. 1999 Feb;107 (Suppl 1):59–64. doi: 10.1289/ehp.99107s159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Broide R. S., Robertson R. T., Leslie F. M. Regulation of alpha7 nicotinic acetylcholine receptors in the developing rat somatosensory cortex by thalamocortical afferents. J Neurosci. 1996 May 1;16(9):2956–2971. doi: 10.1523/JNEUROSCI.16-09-02956.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buznikov G. A., Shmukler Y. B., Lauder J. M. From oocyte to neuron: do neurotransmitters function in the same way throughout development? Cell Mol Neurobiol. 1996 Oct;16(5):537–559. doi: 10.1007/BF02152056. [DOI] [PubMed] [Google Scholar]
  10. Conklin B. R., Brann M. R., Buckley N. J., Ma A. L., Bonner T. I., Axelrod J. Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned genes for muscarinic receptor subtypes stably expressed in A9 L cells. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8698–8702. doi: 10.1073/pnas.85.22.8698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Daubas P., Devillers-Thiéry A., Geoffroy B., Martinez S., Bessis A., Changeux J. P. Differential expression of the neuronal acetylcholine receptor alpha 2 subunit gene during chick brain development. Neuron. 1990 Jul;5(1):49–60. doi: 10.1016/0896-6273(90)90032-b. [DOI] [PubMed] [Google Scholar]
  12. Deneris E. S., Connolly J., Rogers S. W., Duvoisin R. Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors. Trends Pharmacol Sci. 1991 Jan;12(1):34–40. doi: 10.1016/0165-6147(91)90486-c. [DOI] [PubMed] [Google Scholar]
  13. Falugi C. Localization and possible role of molecules associated with the cholinergic system during "non-nervous" developmental events. Eur J Histochem. 1993;37(4):287–294. [PubMed] [Google Scholar]
  14. Frotscher M., Schlander M., Léránth C. Cholinergic neurons in the hippocampus. A combined light- and electron-microscopic immunocytochemical study in the rat. Cell Tissue Res. 1986;246(2):293–301. doi: 10.1007/BF00215891. [DOI] [PubMed] [Google Scholar]
  15. Goldman D., Deneris E., Luyten W., Kochhar A., Patrick J., Heinemann S. Members of a nicotinic acetylcholine receptor gene family are expressed in different regions of the mammalian central nervous system. Cell. 1987 Mar 27;48(6):965–973. doi: 10.1016/0092-8674(87)90705-7. [DOI] [PubMed] [Google Scholar]
  16. Gu Q., Singer W. Effects of intracortical infusion of anticholinergic drugs on neuronal plasticity in kitten striate cortex. Eur J Neurosci. 1993 May 1;5(5):475–485. doi: 10.1111/j.1460-9568.1993.tb00514.x. [DOI] [PubMed] [Google Scholar]
  17. Gutkind J. S., Novotny E. A., Brann M. R., Robbins K. C. Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4703–4707. doi: 10.1073/pnas.88.11.4703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ha D. H., Robertson R. T., Weiss J. H. Distinctive morphological features of a subset of cortical neurons grown in the presence of basal forebrain neurons in vitro. J Neurosci. 1998 Jun 1;18(11):4201–4215. doi: 10.1523/JNEUROSCI.18-11-04201.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hankin M. H., Hoover F., Goldman D. Cues intrinsic to the retina induce nAChR gene expression during development. J Neurobiol. 1993 Aug;24(8):1099–1110. doi: 10.1002/neu.480240808. [DOI] [PubMed] [Google Scholar]
  20. Hohmann C. F., Brooks A. R., Coyle J. T. Neonatal lesions of the basal forebrain cholinergic neurons result in abnormal cortical development. Brain Res. 1988 Aug 1;470(2):253–264. doi: 10.1016/0165-3806(88)90244-1. [DOI] [PubMed] [Google Scholar]
  21. Hohmann C. F., Potter E. D., Levey A. I. Development of muscarinic receptor subtypes in the forebrain of the mouse. J Comp Neurol. 1995 Jul 17;358(1):88–101. doi: 10.1002/cne.903580106. [DOI] [PubMed] [Google Scholar]
  22. Hubel D. H., Wiesel T. N. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J Physiol. 1970 Feb;206(2):419–436. doi: 10.1113/jphysiol.1970.sp009022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Höhmann C. F., Kwiterovich K. K., Oster-Granite M. L., Coyle J. T. Newborn basal forebrain lesions disrupt cortical cytodifferentiation as visualized by rapid Golgi staining. Cereb Cortex. 1991 Mar-Apr;1(2):143–157. doi: 10.1093/cercor/1.2.143. [DOI] [PubMed] [Google Scholar]
  24. Höhmann C. F., Pert C. C., Ebner F. F. Development of cholinergic markers in mouse forebrain. II. Muscarinic receptor binding in cortex. Brain Res. 1985 Dec;355(2):243–253. doi: 10.1016/0165-3806(85)90046-x. [DOI] [PubMed] [Google Scholar]
  25. Höhmann C. F., Wilson L., Coyle J. T. Efferent and afferent connections of mouse sensory-motor cortex following cholinergic deafferentation at birth. Cereb Cortex. 1991 Mar-Apr;1(2):158–172. doi: 10.1093/cercor/1.2.158. [DOI] [PubMed] [Google Scholar]
  26. Johnston M. V., Hohmann C., Blue M. E. Neurobiology of Rett syndrome. Neuropediatrics. 1995 Apr;26(2):119–122. doi: 10.1055/s-2007-979740. [DOI] [PubMed] [Google Scholar]
  27. Juliano S. L., Ma W., Bear M. F., Eslin D. Cholinergic manipulation alters stimulus-evoked metabolic activity in cat somatosensory cortex. J Comp Neurol. 1990 Jul 1;297(1):106–120. doi: 10.1002/cne.902970108. [DOI] [PubMed] [Google Scholar]
  28. Kinney H. C., O'Donnell T. J., Kriger P., White W. F. Early developmental changes in [3H]nicotine binding in the human brainstem. Neuroscience. 1993 Aug;55(4):1127–1138. doi: 10.1016/0306-4522(93)90326-b. [DOI] [PubMed] [Google Scholar]
  29. Kumar A., Schliebs R. Postnatal laminar development of cholinergic receptors, protein kinase C and dihydropyridine-sensitive calcium antagonist binding in rat visual cortex. Effect of visual deprivation. Int J Dev Neurosci. 1992 Dec;10(6):491–504. doi: 10.1016/0736-5748(92)90050-a. [DOI] [PubMed] [Google Scholar]
  30. Laasberg T., Pedak A., Neuman T. The muscarinic receptor-mediated action of acetylcholine in the gastrulating chick embryo. Comp Biochem Physiol C. 1987;86(2):313–316. doi: 10.1016/0742-8413(87)90085-5. [DOI] [PubMed] [Google Scholar]
  31. Larocca J. N., Rodriguez-Gabin A. G., Rashbaum W. K., Weidenheim K. M., Lyman W. D. Muscarinic receptor-dependent activation of phospholipase C in the developing human fetal central nervous system. Brain Res. 1994 Aug 8;653(1-2):9–15. doi: 10.1016/0006-8993(94)90365-4. [DOI] [PubMed] [Google Scholar]
  32. Lauder J. M. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 1993 Jun;16(6):233–240. doi: 10.1016/0166-2236(93)90162-f. [DOI] [PubMed] [Google Scholar]
  33. Lauder J. M. Neurotransmitters as morphogens. Prog Brain Res. 1988;73:365–387. doi: 10.1016/S0079-6123(08)60516-6. [DOI] [PubMed] [Google Scholar]
  34. Levey A. I., Wainer B. H., Rye D. B., Mufson E. J., Mesulam M. M. Choline acetyltransferase-immunoreactive neurons intrinsic to rodent cortex and distinction from acetylcholinesterase-positive neurons. Neuroscience. 1984 Oct;13(2):341–353. doi: 10.1016/0306-4522(84)90234-3. [DOI] [PubMed] [Google Scholar]
  35. Lichtensteiger W., Ribary U., Schlumpf M., Odermatt B., Widmer H. R. Prenatal adverse effects of nicotine on the developing brain. Prog Brain Res. 1988;73:137–157. doi: 10.1016/S0079-6123(08)60502-6. [DOI] [PubMed] [Google Scholar]
  36. Lipton S. A., Frosch M. P., Phillips M. D., Tauck D. L., Aizenman E. Nicotinic antagonists enhance process outgrowth by rat retinal ganglion cells in culture. Science. 1988 Mar 11;239(4845):1293–1296. doi: 10.1126/science.3344435. [DOI] [PubMed] [Google Scholar]
  37. Lipton S. A., Kater S. B. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci. 1989 Jul;12(7):265–270. doi: 10.1016/0166-2236(89)90026-x. [DOI] [PubMed] [Google Scholar]
  38. Liu Y., Jia W., Gu Q., Cynader M. Involvement of muscarinic acetylcholine receptors in regulation of kitten visual cortex plasticity. Brain Res Dev Brain Res. 1994 May 13;79(1):63–71. doi: 10.1016/0165-3806(94)90049-3. [DOI] [PubMed] [Google Scholar]
  39. Matter J. M., Matter-Sadzinski L., Ballivet M. Expression of neuronal nicotinic acetylcholine receptor genes in the developing chick visual system. EMBO J. 1990 Apr;9(4):1021–1026. doi: 10.1002/j.1460-2075.1990.tb08205.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Mattson M. P. Neurotransmitters in the regulation of neuronal cytoarchitecture. Brain Res. 1988 Apr-Jun;472(2):179–212. doi: 10.1016/0165-0173(88)90020-3. [DOI] [PubMed] [Google Scholar]
  41. McCobb D. P., Cohan C. S., Connor J. A., Kater S. B. Interactive effects of serotonin and acetylcholine on neurite elongation. Neuron. 1988 Jul;1(5):377–385. doi: 10.1016/0896-6273(88)90187-0. [DOI] [PubMed] [Google Scholar]
  42. McKenzie F. R., Seuwen K., Pouysségur J. Stimulation of phosphatidylcholine breakdown by thrombin and carbachol but not by tyrosine kinase receptor ligands in cells transfected with M1 muscarinic receptors. Rapid desensitization of phosphocholine-specific (PC) phospholipase D but sustained activity of PC-phospholipase C. J Biol Chem. 1992 Nov 15;267(32):22759–22769. [PubMed] [Google Scholar]
  43. Messi M. L., Renganathan M., Grigorenko E., Delbono O. Activation of alpha7 nicotinic acetylcholine receptor promotes survival of spinal cord motoneurons. FEBS Lett. 1997 Jul 7;411(1):32–38. doi: 10.1016/s0014-5793(97)00600-5. [DOI] [PubMed] [Google Scholar]
  44. Rand J. B., Russell R. L. Choline acetyltransferase-deficient mutants of the nematode Caenorhabditis elegans. Genetics. 1984 Feb;106(2):227–248. doi: 10.1093/genetics/106.2.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reich A., Drews U. Choline acetyltransferase in the chick limb bud. Histochemistry. 1983;78(3):383–389. doi: 10.1007/BF00496624. [DOI] [PubMed] [Google Scholar]
  46. Rossner S., Kues W., Witzemann V., Schliebs R. Laminar expression of m1-, m3- and m4-muscarinic cholinergic receptor genes in the developing rat visual cortex using in situ hybridization histochemistry. Effect of monocular visual deprivation. Int J Dev Neurosci. 1993 Jun;11(3):369–378. doi: 10.1016/0736-5748(93)90008-2. [DOI] [PubMed] [Google Scholar]
  47. Rossner S., Kumar A., Witzemann V., Schliebs R. Development of laminar expression of the m2 muscarinic cholinergic receptor gene in rat visual cortex and the effect of monocular visual deprivation. Brain Res Dev Brain Res. 1994 Jan 14;77(1):55–61. doi: 10.1016/0165-3806(94)90213-5. [DOI] [PubMed] [Google Scholar]
  48. Schambra U. B., Lauder J. M., Petrusz P., Sulik K. K. Development of neurotransmitter systems in the mouse embryo following acute ethanol exposure: a histological and immunocytochemical study. Int J Dev Neurosci. 1990;8(5):507–522. doi: 10.1016/0736-5748(90)90043-2. [DOI] [PubMed] [Google Scholar]
  49. Schambra U. B., Sulik K. K., Petrusz P., Lauder J. M. Ontogeny of cholinergic neurons in the mouse forebrain. J Comp Neurol. 1989 Oct 1;288(1):101–122. doi: 10.1002/cne.902880109. [DOI] [PubMed] [Google Scholar]
  50. Schlumpf M., Palacios J. M., Cortes R., Lichtensteiger W. Regional development of muscarinic cholinergic binding sites in the prenatal rat brain. Neuroscience. 1991;45(2):347–357. doi: 10.1016/0306-4522(91)90232-d. [DOI] [PubMed] [Google Scholar]
  51. Schmidt H. Muscarinic acetylcholine receptor in chick limb bud during morphogeneis. Histochemistry. 1981;71(1):89–98. doi: 10.1007/BF00592573. [DOI] [PubMed] [Google Scholar]
  52. Slotkin T. A. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect. 1999 Feb;107 (Suppl 1):71–80. doi: 10.1289/ehp.99107s171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Soreq H., Patinkin D., Lev-Lehman E., Grifman M., Ginzberg D., Eckstein F., Zakut H. Antisense oligonucleotide inhibition of acetylcholinesterase gene expression induces progenitor cell expansion and suppresses hematopoietic apoptosis ex vivo. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):7907–7911. doi: 10.1073/pnas.91.17.7907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Vilaró M. T., Wiederhold K. H., Palacios J. M., Mengod G. Muscarinic M2 receptor mRNA expression and receptor binding in cholinergic and non-cholinergic cells in the rat brain: a correlative study using in situ hybridization histochemistry and receptor autoradiography. Neuroscience. 1992;47(2):367–393. doi: 10.1016/0306-4522(92)90253-x. [DOI] [PubMed] [Google Scholar]
  55. Wee E. L., Phillips N. J., Babiarz B. S., Zimmerman E. F. Palate morphogenesis. V. Effects of cholinergic agonists and antagonists on rotation in embryo culture. J Embryol Exp Morphol. 1980 Aug;58:177–193. [PubMed] [Google Scholar]
  56. Wiesel T. N., Hubel D. H. Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J Neurophysiol. 1965 Nov;28(6):1029–1040. doi: 10.1152/jn.1965.28.6.1029. [DOI] [PubMed] [Google Scholar]
  57. Wotta D. R., Wattenberg E. V., Langason R. B., el-Fakahany E. E. M1, M3 and M5 muscarinic receptors stimulate mitogen-activated protein kinase. Pharmacology. 1998 Apr;56(4):175–186. doi: 10.1159/000028196. [DOI] [PubMed] [Google Scholar]
  58. von der Kammer H., Mayhaus M., Albrecht C., Enderich J., Wegner M., Nitsch R. M. Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors. J Biol Chem. 1998 Jun 5;273(23):14538–14544. doi: 10.1074/jbc.273.23.14538. [DOI] [PubMed] [Google Scholar]

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