Skip to main content
PMC home page
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
. 1996 Mar 5;93(5):1808–1813. doi: 10.1073/pnas.93.5.1808

Steel mutant mice are deficient in hippocampal learning but not long-term potentiation.

B Motro 1, J M Wojtowicz 1, A Bernstein 1, D van der Kooy 1
PMCID: PMC39863  PMID: 8700840

Abstract

Mice carrying mutations in either the dominant white-spotting (W) or Steel (Sl) loci exhibit deficits in melanogenesis, gametogenesis, and hematopoiesis. W encodes the Kit receptor tyrosine kinase, while Sl encodes the Kit ligand, Steel factor, and the receptor-ligand pair are contiguously expressed at anatomical sites expected from the phenotypes of W and Sl mice. The c-kit and Steel genes are also both highly expressed in the adult murine hippocampus: Steel is expressed in dentate gyrus neurons whose mossy fiber axons synapse with the c-kit expressing CA3 pyramidal neurons. We report here that Sl/Sld mutant mice have a specific deficit in spatial learning. These mutant mice are also deficient in baseline synaptic transmission between the dentate gyrus and CA3 but show normal long-term potentiation in this pathway. These observations demonstrate a role for Steel factor/Kit signaling in the adult nervous system and suggest that a severe deficit in hippocampal-dependent learning need not be associated with reduced hippocampal long-term potentiation.

Full text

PDF
1808

Selected References

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

  1. Abeliovich A., Chen C., Goda Y., Silva A. J., Stevens C. F., Tonegawa S. Modified hippocampal long-term potentiation in PKC gamma-mutant mice. Cell. 1993 Dec 31;75(7):1253–1262. doi: 10.1016/0092-8674(93)90613-u. [DOI] [PubMed] [Google Scholar]
  2. Abeliovich A., Paylor R., Chen C., Kim J. J., Wehner J. M., Tonegawa S. PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell. 1993 Dec 31;75(7):1263–1271. doi: 10.1016/0092-8674(93)90614-v. [DOI] [PubMed] [Google Scholar]
  3. Barnes C. A., Jung M. W., McNaughton B. L., Korol D. L., Andreasson K., Worley P. F. LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J Neurosci. 1994 Oct;14(10):5793–5806. doi: 10.1523/JNEUROSCI.14-10-05793.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barnes C. A. Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat. Trends Neurosci. 1988 Apr;11(4):163–169. doi: 10.1016/0166-2236(88)90143-9. [DOI] [PubMed] [Google Scholar]
  5. Bliss T. V., Collingridge G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993 Jan 7;361(6407):31–39. doi: 10.1038/361031a0. [DOI] [PubMed] [Google Scholar]
  6. Bliss T. V., Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973 Jul;232(2):331–356. doi: 10.1113/jphysiol.1973.sp010273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brannan C. I., Lyman S. D., Williams D. E., Eisenman J., Anderson D. M., Cosman D., Bedell M. A., Jenkins N. A., Copeland N. G. Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4671–4674. doi: 10.1073/pnas.88.11.4671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Castro C. A., Silbert L. H., McNaughton B. L., Barnes C. A. Recovery of spatial learning deficits after decay of electrically induced synaptic enhancement in the hippocampus. Nature. 1989 Nov 30;342(6249):545–548. doi: 10.1038/342545a0. [DOI] [PubMed] [Google Scholar]
  9. Chabot B., Stephenson D. A., Chapman V. M., Besmer P., Bernstein A. The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature. 1988 Sep 1;335(6185):88–89. doi: 10.1038/335088a0. [DOI] [PubMed] [Google Scholar]
  10. Claiborne B. J., Xiang Z., Brown T. H. Hippocampal circuitry complicates analysis of long-term potentiation in mossy fiber synapses. Hippocampus. 1993 Apr;3(2):115–121. doi: 10.1002/hipo.450030202. [DOI] [PubMed] [Google Scholar]
  11. Copeland N. G., Gilbert D. J., Cho B. C., Donovan P. J., Jenkins N. A., Cosman D., Anderson D., Lyman S. D., Williams D. E. Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles. Cell. 1990 Oct 5;63(1):175–183. doi: 10.1016/0092-8674(90)90298-s. [DOI] [PubMed] [Google Scholar]
  12. Davis S., Butcher S. P., Morris R. G. The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J Neurosci. 1992 Jan;12(1):21–34. doi: 10.1523/JNEUROSCI.12-01-00021.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Davis S., Butcher S. P., Morris R. G. The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J Neurosci. 1992 Jan;12(1):21–34. doi: 10.1523/JNEUROSCI.12-01-00021.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Drake C. T., Terman G. W., Simmons M. L., Milner T. A., Kunkel D. D., Schwartzkroin P. A., Chavkin C. Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters. J Neurosci. 1994 Jun;14(6):3736–3750. doi: 10.1523/JNEUROSCI.14-06-03736.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Eichenbaum H., Otto T., Cohen N. J. The hippocampus--what does it do? Behav Neural Biol. 1992 Jan;57(1):2–36. doi: 10.1016/0163-1047(92)90724-i. [DOI] [PubMed] [Google Scholar]
  16. Flanagan J. G., Chan D. C., Leder P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell. 1991 Mar 8;64(5):1025–1035. doi: 10.1016/0092-8674(91)90326-t. [DOI] [PubMed] [Google Scholar]
  17. Fleischman R. A., Saltman D. L., Stastny V., Zneimer S. Deletion of the c-kit protooncogene in the human developmental defect piebald trait. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10885–10889. doi: 10.1073/pnas.88.23.10885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Frey U., Huang Y. Y., Kandel E. R. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science. 1993 Jun 11;260(5114):1661–1664. doi: 10.1126/science.8389057. [DOI] [PubMed] [Google Scholar]
  19. Geissler E. N., Ryan M. A., Housman D. E. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell. 1988 Oct 7;55(1):185–192. doi: 10.1016/0092-8674(88)90020-7. [DOI] [PubMed] [Google Scholar]
  20. Grant S. G., O'Dell T. J., Karl K. A., Stein P. L., Soriano P., Kandel E. R. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992 Dec 18;258(5090):1903–1910. doi: 10.1126/science.1361685. [DOI] [PubMed] [Google Scholar]
  21. Hanse Eric, Gustafsson Bengt. Long-term Potentiation and Field EPSPs in the Lateral and Medial Perforant Paths in the Dentate Gyrus In Vitro: a Comparison. Eur J Neurosci. 1992 Oct;4(11):1191–1201. doi: 10.1111/j.1460-9568.1992.tb00144.x. [DOI] [PubMed] [Google Scholar]
  22. Huang E., Nocka K., Beier D. R., Chu T. Y., Buck J., Lahm H. W., Wellner D., Leder P., Besmer P. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990 Oct 5;63(1):225–233. doi: 10.1016/0092-8674(90)90303-v. [DOI] [PubMed] [Google Scholar]
  23. Huizinga J. D., Thuneberg L., Klüppel M., Malysz J., Mikkelsen H. B., Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature. 1995 Jan 26;373(6512):347–349. doi: 10.1038/373347a0. [DOI] [PubMed] [Google Scholar]
  24. Hultén M. A., Honeyman M. M., Mayne A. J., Tarlow M. J. Homozygosity in piebald trait. J Med Genet. 1987 Sep;24(9):568–571. doi: 10.1136/jmg.24.9.568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jeffery K. J., Morris R. G. Cumulative long-term potentiation in the rat dentate gyrus correlates with, but does not modify, performance in the water maze. Hippocampus. 1993 Apr;3(2):133–140. doi: 10.1002/hipo.450030205. [DOI] [PubMed] [Google Scholar]
  26. Keller B. U., Konnerth A., Yaari Y. Patch clamp analysis of excitatory synaptic currents in granule cells of rat hippocampus. J Physiol. 1991 Apr;435:275–293. doi: 10.1113/jphysiol.1991.sp018510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Keshet E., Lyman S. D., Williams D. E., Anderson D. M., Jenkins N. A., Copeland N. G., Parada L. F. Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development. EMBO J. 1991 Sep;10(9):2425–2435. doi: 10.1002/j.1460-2075.1991.tb07782.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Korol D. L., Abel T. W., Church L. T., Barnes C. A., McNaughton B. L. Hippocampal synaptic enhancement and spatial learning in the Morris swim task. Hippocampus. 1993 Apr;3(2):127–132. doi: 10.1002/hipo.450030204. [DOI] [PubMed] [Google Scholar]
  29. Matsui Y., Zsebo K. M., Hogan B. L. Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature. 1990 Oct 18;347(6294):667–669. doi: 10.1038/347667a0. [DOI] [PubMed] [Google Scholar]
  30. Morris R. G., Garrud P., Rawlins J. N., O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982 Jun 24;297(5868):681–683. doi: 10.1038/297681a0. [DOI] [PubMed] [Google Scholar]
  31. Motro B., van der Kooy D., Rossant J., Reith A., Bernstein A. Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci. Development. 1991 Dec;113(4):1207–1221. doi: 10.1242/dev.113.4.1207. [DOI] [PubMed] [Google Scholar]
  32. Orr-Urtreger A., Avivi A., Zimmer Y., Givol D., Yarden Y., Lonai P. Developmental expression of c-kit, a proto-oncogene encoded by the W locus. Development. 1990 Aug;109(4):911–923. doi: 10.1242/dev.109.4.911. [DOI] [PubMed] [Google Scholar]
  33. Schenk F., Morris R. G. Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions. Exp Brain Res. 1985;58(1):11–28. doi: 10.1007/BF00238949. [DOI] [PubMed] [Google Scholar]
  34. Schwegler H., Lipp H. P. Hereditary covariations of neuronal circuitry and behavior: correlations between the proportions of hippocampal synaptic fields in the regio inferior and two-way avoidance in mice and rats. Behav Brain Res. 1983 Jan;7(1):1–38. doi: 10.1016/0166-4328(83)90002-5. [DOI] [PubMed] [Google Scholar]
  35. Silva A. J., Paylor R., Wehner J. M., Tonegawa S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):206–211. doi: 10.1126/science.1321493. [DOI] [PubMed] [Google Scholar]
  36. Silva A. J., Stevens C. F., Tonegawa S., Wang Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):201–206. doi: 10.1126/science.1378648. [DOI] [PubMed] [Google Scholar]
  37. Squire L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev. 1992 Apr;99(2):195–231. doi: 10.1037/0033-295x.99.2.195. [DOI] [PubMed] [Google Scholar]
  38. Sutherland R. J., Dringenberg H. C., Hoesing J. M. Induction of long-term potentiation at perforant path dentate synapses does not affect place learning or memory. Hippocampus. 1993 Apr;3(2):141–147. doi: 10.1002/hipo.450030206. [DOI] [PubMed] [Google Scholar]
  39. Sutherland R. J., McDonald R. J. Hippocampus, amygdala, and memory deficits in rats. Behav Brain Res. 1990 Feb 12;37(1):57–79. doi: 10.1016/0166-4328(90)90072-m. [DOI] [PubMed] [Google Scholar]
  40. Sutherland R. J., Whishaw I. Q., Kolb B. A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat. Behav Brain Res. 1983 Feb;7(2):133–153. doi: 10.1016/0166-4328(83)90188-2. [DOI] [PubMed] [Google Scholar]
  41. Sutherland R. J., Whishaw I. Q., Kolb B. Contributions of cingulate cortex to two forms of spatial learning and memory. J Neurosci. 1988 Jun;8(6):1863–1872. doi: 10.1523/JNEUROSCI.08-06-01863.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Telfer M. A., Sugar M., Jaeger E. A., Mulcahy J. Dominant piebald trait (white forelock and leukoderma) with neurological impairment. Am J Hum Genet. 1971 Jul;23(4):383–389. [PMC free article] [PubMed] [Google Scholar]
  43. Upchurch M., Wehner J. M. Differences between inbred strains of mice in Morris water maze performance. Behav Genet. 1988 Jan;18(1):55–68. doi: 10.1007/BF01067075. [DOI] [PubMed] [Google Scholar]
  44. Weisskopf M. G., Zalutsky R. A., Nicoll R. A. The opioid peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fibre synapses and modulates long-term potentiation. Nature. 1993 Apr 1;362(6419):423–427. doi: 10.1038/362423a0. [DOI] [PubMed] [Google Scholar]
  45. Wigström H., Gustafsson B. Facilitated induction of hippocampal long-lasting potentiation during blockade of inhibition. Nature. 1983 Feb 17;301(5901):603–604. doi: 10.1038/301603a0. [DOI] [PubMed] [Google Scholar]
  46. Zsebo K. M., Williams D. A., Geissler E. N., Broudy V. C., Martin F. H., Atkins H. L., Hsu R. Y., Birkett N. C., Okino K. H., Murdock D. C. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990 Oct 5;63(1):213–224. doi: 10.1016/0092-8674(90)90302-u. [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