Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1981 Jul;78(7):4630–4634. doi: 10.1073/pnas.78.7.4630

Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation.

P Levitt, J L Noebels
PMCID: PMC319847  PMID: 6945603

Abstract

The central catecholamine neuron system in the mutant mouse tottering was examined by fluorescence histochemistry and biochemical analysis of catecholamine content. This single-locus neurological mutation expresses a reproducible alteration in central nervous system physiology characterized by spontaneous spike-wave and focal motor seizures in the absence of any previously recognized disturbance of cellular organization or brain size. Histochemical analysis showed a significant increase in the number of noradrenergic axons in terminal fields innervated by the nucleus locus ceruleus when compared with the wild type. A concomitant 100-200% rise in norepinephrine levels is found in the same areas, including hippocampus, cerebellum, and dorsal lateral geniculate. Catecholamine fibers and transmitter content in areas innervated by a second major noradrenergic system arising from the brainstem lateral tegmental neurons are unaltered. The terminal axons and transmitter content were both unchanged in nuclei receiving a dense dopaminergic innervation. Despite the hypertrophy of the locus ceruleus axonal plexus, the number and size of locus ceruleus cell somata were identical in both wild-type and tottering mice. These findings are consistent with a specific gene-linked alteration of developmental events controlling the number of axons produced by a single neuronal population in the mammalian brain.

Full text

PDF
4633

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson G. M., Batter D. K., Young J. G., Shaywitz B. A., Cohen D. J. Simplified liquid chromatographic--electrochemical determination of norepinephrine and dopamine in rat brain. J Chromatogr. 1980 Mar 14;181(3-4):453–455. doi: 10.1016/s0378-4347(00)81148-2. [DOI] [PubMed] [Google Scholar]
  2. Baker H., Joh T. H., Reis D. J. Genetic control of number of midbrain dopaminergic neurons in inbred strains of mice: relationship to size and neuronal density of the striatum. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4369–4373. doi: 10.1073/pnas.77.7.4369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berger B., Hervé D., Dolphin A., Barthelemy C., Gay M., Tassin J. P. Genetically determined differences in noradrenergic input to the brain cortex: a histochemical and biochemical study in two inbred strains of mice. Neuroscience. 1979;4(7):877–888. doi: 10.1016/0306-4522(79)90172-6. [DOI] [PubMed] [Google Scholar]
  4. Black I. B. Abnormal brain catecholamine enzymes in Weaver mutant mice. Brain Res. 1976 Apr 9;105(3):602–605. doi: 10.1016/0006-8993(76)90612-0. [DOI] [PubMed] [Google Scholar]
  5. Caviness V. S., Jr, Rakic P. Mechanisms of cortical development: a view from mutations in mice. Annu Rev Neurosci. 1978;1:297–326. doi: 10.1146/annurev.ne.01.030178.001501. [DOI] [PubMed] [Google Scholar]
  6. Ciaranello R. D., Hoffman H. J., Shire J. G., Axelrod J. Genetic regulation of the catecholamine biosynthetic enzymes. II. Inheritance of tyrosine hydroxylase, dopamine-beta-hydroxylase, and phenylethanolamine N-methyltransferase. J Biol Chem. 1974 Jul 25;249(14):4528–4536. [PubMed] [Google Scholar]
  7. Fallon J. H., Moore R. Y. Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum. J Comp Neurol. 1978 Aug 1;180(3):545–580. doi: 10.1002/cne.901800310. [DOI] [PubMed] [Google Scholar]
  8. GREEN M. C., SIDMAN R. L. Tottering--a neuromusclar mutation in the mouse. And its linkage with oligosyndacylism. J Hered. 1962 Sep-Oct;53:233–237. doi: 10.1093/oxfordjournals.jhered.a107180. [DOI] [PubMed] [Google Scholar]
  9. Grzanna R., Molliver M. E., Coyle J. T. Visualization of central noradrenergic neurons in thick sections by the unlabeled antibody method: a transmitter-specific Golgi image. Proc Natl Acad Sci U S A. 1978 May;75(5):2502–2506. doi: 10.1073/pnas.75.5.2502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Johnston M. V., Grzanna R., Coyle J. T. Methylazoxymethanol treatment of fetal rats results in abnormally dense noradrenergic innervation of neocortex. Science. 1979 Jan 26;203(4378):369–371. doi: 10.1126/science.32620. [DOI] [PubMed] [Google Scholar]
  11. Kromer L. F., Moore R. Y. A study of the organization of the locus coeruleus projections to the lateral geniculate nuclei in the albino rat. Neuroscience. 1980;5(2):255–271. doi: 10.1016/0306-4522(80)90102-5. [DOI] [PubMed] [Google Scholar]
  12. Kromer L. F., Moore R. Y. Norepinephrine innervation of the cochlear nuclei by locus coeruleus neurons in the rat. Anat Embryol (Berl) 1980;158(2):227–244. doi: 10.1007/BF00315908. [DOI] [PubMed] [Google Scholar]
  13. Landis S. C., Shoemaker W. J., Schlumpf M., Bloom F. E. Catecholamines in mutant mouse cerebellum: fluorescence microscopic and chemical studies. Brain Res. 1975 Aug 8;93(2):253–266. doi: 10.1016/0006-8993(75)90349-2. [DOI] [PubMed] [Google Scholar]
  14. Lane J. D., Nadi N. S., McBride W. J., Aprison M. H., Kusano K. Contents of serotonin, norepinephrine and dopamine in the cerebrum of the "staggerer", "weaver" and "nervous" neurologically mutant mice. J Neurochem. 1977 Aug;29(2):349–350. doi: 10.1111/j.1471-4159.1977.tb09629.x. [DOI] [PubMed] [Google Scholar]
  15. Levitt P., Moore R. Y. Organization of brainstem noradrenaline hyperinnervation following neonatal 6-hydroxydopamine treatment in rat. Anat Embryol (Berl) 1980;158(2):133–150. doi: 10.1007/BF00315901. [DOI] [PubMed] [Google Scholar]
  16. Levitt P., Moore R. Y. Origin and organization of brainstem catecholamine innervation in the rat. J Comp Neurol. 1979 Aug 15;186(4):505–528. doi: 10.1002/cne.901860402. [DOI] [PubMed] [Google Scholar]
  17. Lindvall O., Björklund A. The organization of the ascending catecholamine neuron systems in the rat brain as revealed by the glyoxylic acid fluorescence method. Acta Physiol Scand Suppl. 1974;412:1–48. [PubMed] [Google Scholar]
  18. Loy R., Koziell D. A., Lindsey J. D., Moore R. Y. Noradrenergic innervation of the adult rat hippocampal formation. J Comp Neurol. 1980 Feb 15;189(4):699–710. doi: 10.1002/cne.901890406. [DOI] [PubMed] [Google Scholar]
  19. Moore R. Y., Bloom F. E. Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. Annu Rev Neurosci. 1978;1:129–169. doi: 10.1146/annurev.ne.01.030178.001021. [DOI] [PubMed] [Google Scholar]
  20. Moore R. Y., Bloom F. E. Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci. 1979;2:113–168. doi: 10.1146/annurev.ne.02.030179.000553. [DOI] [PubMed] [Google Scholar]
  21. Moore R. Y. Catecholamin innervation of the basal forebrain. I. The septal area. J Comp Neurol. 1978 Feb 15;177(4):665–684. doi: 10.1002/cne.901770408. [DOI] [PubMed] [Google Scholar]
  22. Noebels J. L. Analysis of inherited epilepsy using single locus mutations in mice. Fed Proc. 1979 Sep;38(10):2405–2410. [PubMed] [Google Scholar]
  23. Noebels J. L., Sidman R. L. Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science. 1979 Jun 22;204(4399):1334–1336. doi: 10.1126/science.572084. [DOI] [PubMed] [Google Scholar]
  24. Pickel V. M., Segal M., Bloom F. E. Axanol proliferation following lesions of cerebellar peduncles. A combined fluorescence microscopic and radioautographic study. J Comp Neurol. 1974 May 1;155(1):43–60. doi: 10.1002/cne.901550104. [DOI] [PubMed] [Google Scholar]
  25. Ross R. A., Judd A. B., Pickel V. M., Joh T. H., Reis D. J. Strain-dependent variations in number of midbrain dopaminergic neurones. Nature. 1976 Dec 16;264(5587):654–656. doi: 10.1038/264654a0. [DOI] [PubMed] [Google Scholar]
  26. Sachs C., Jonsson G. Effects of 6-hydroxydopamine on central noradrenaline neurons during ontogeny. Brain Res. 1975 Dec 5;99(2):277–291. doi: 10.1016/0006-8993(75)90029-3. [DOI] [PubMed] [Google Scholar]
  27. Swanson L. W., Hartman B. K. The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol. 1975 Oct 15;163(4):467–505. doi: 10.1002/cne.901630406. [DOI] [PubMed] [Google Scholar]
  28. Torre J. C., Surgeon J. W. A methodological approach to rapid and sensitive monoamine histofluorescence using a modified glyoxylic acid technique: the SPG method. Histochemistry. 1976 Oct 22;49(2):81–93. doi: 10.1007/BF00495672. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES