Cover Image

Not for Sale



View/Hide Left Panel

injury in which microglia attach to the dendrites and displace and then remove synaptic boutons (113, 114). In the injured hamster facial nucleus, the testosterone attenuated the amount of synaptic stripping while increasing regeneration of facial nucleus neurons (115).

Conclusions: A Model of Estrogen Action

Our current knowledge of ovarian hormone actions on hippocampal synapse formation and breakdown has led us to a testable, working model (Fig. 8) in which possible sites of E action are delineated in relation to the location of nuclear and non-nuclear ER. The present discussion pertains to ERa, but further studies of ERß may reveal that it is also present in non-nuclear sites within the hippocampus and may participate in some of the processes outlined in Fig. 8. ER in the dendritic spine may be associated with the activation of mRNA translation from polyribosomes (100, 101) or endomembrane structures found in spines (116). In addition, other second messenger signaling effects might include the phosphorylation of neurotransmitter receptors or ion channels. ER in certain presynaptic terminals might modulate neurotransmitter release(4951) or reuptake (52). In addition, ER-mediated activation of second messenger systems in dendritic spines and presynaptic endings might lead to retrograde signal transduction back to the cell nucleus, perhaps via Akt or CREB, providing another pathway through which E could regulate gene expression. In addition, as noted above, ER in glial cells might modulate both the formation of constituents of the plasma membrane or the induction of progestin receptors, activation of which may be involved in synapse down-regulation. We consider that these postulated actions of E operate synergistically with the actions of E via nuclear receptors in interneurons, discussed above, that modulate the inhibitory tone on the CA1 pyramidal neurons where synapse formation occurs.

Research support is acknowledged from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS 070880) and from the National Institute on Aging (PO1AG16765) to B.M.

1. Chadwick, D.J. & Goode, J.A. (2000) Neuronal and Cognitive Effects of Oestrogens (Wiley, London).

2. McEwen, B.S. & Alves, S.H. (1999) Endocr. Rev. 20, 279–307.

3. Weiland, N.G., Orikasa, C., Hayashi, S. & McEwen, B.S. (1997) J. Comp. Neurol. 388, 603–612.

4. Woolley, C., Gould, E., Frankfurt, M. & McEwen, B.S. (1990) J. Neurosci. 10, 4035–4039.

5. Carrer, H. & Aoki, A. (1982) Brain Res. 240, 221–233.

6. Frankfurt, M., Gould, E., Wolley, C. & McEwen, B.S. (1990) Neuroendocrinology 51, 530–535.

7. Calizo, L.H. & Flanagan-Cato, L.M. (2000) J. Neurosci. 20, 1589–1596.

8. Pfaff, D.W. (1980) Estrogens and Brain Function (Springer, New York).

9. Sandstrom, N.J. & Williams, C.L. (2000) Behav. Neurosci., 115, 384–393.

10. Sherwin, B.B. & Tulandi, T. (1996) J. Clin. Endocrinol. Metab. 81, 2545–2549.

11. Milner, T.A., McEwen, B.S., Hayashi, S., Li, C.J., Reagen, L. & Alves, S.E. (2001) J. Comp. Neurol. 429, 355–371.

12. Levin, E.R. (1999) Trends Endocrinol. Metab. 10, 374–377.

13. Kelly, M.J. & Wagner, E.J. (1999) Trends Endocrinol. Metab. 10, 369–374.

14. Simoncini, T., Hafezi-Moghadam, A., Brazil, D.P., Ley, K., Chin, W.W. & Liao, J.K. (2000) Nature (London) 407, 538–541.

15. Wong, M. & Moss, R.L. (1992) J. Neurosci. 12, 3217–3225.

16. Wong, M. & Moss, R.L. (1991) Brain Res. 543, 148–152.

17. Woolley, C.S., Weiland, N.G., McEwen, B.S. & Schwartzkroin, P.A. (1997) J. Neurosci. 17, 1848–1859.

18. Warren, S.G., Humphreys, A.G., Juraska, J.M. & Greenough, W.T. (1995) Brain Res. 703, 26–30.

19. Terasawa, E. & Timiras, P. (1968) Endocrinology 83, 207–216.

20. Takumi, Y., Ramirez-Leon, V., Laake, P., Rinvik, E. & Ottersen, O.P. (1999) Nat. Neurosci. 2, 618–624.

21. Malgaroli, A. (1999) Nat. Neurosci. 2, 3–5.

22. Woolley, C. & McEwen, B.S. (1994) J. Neurosci. 14, 7680–7687.

23. Fader, A.J., Hendricson, A.W. & Dohanich, G.P. (1998) Neurobiol. Learn. Mem. 69, 225–240.

24. Daniel, J.M., Roberts, S.L. & Dohanich, G.P. (1999) Physiol. Behav. 66, 11–20.

25. O’Neal, M.F., Means, L.W., Poole, M.C. & Hamm, R.J. (1996) Psychoneuroendocrinology 21, 51–65.

26. Luine, V.N., Richards, S.T., Wu, V.Y. & Beck, K.D. (1998) Horm. Behav. 34, 149–162.

27. Sherwin, B.B. (1994) Ann. N.Y.Acad. Sci. 743, 213–231.

28. Woolley, C. & McEwen, B.S. (1992) J. Neurosci. 12, 2549–2554.

29. Gould, E., Woolley, C., Frankfurt, M. & McEwen, B.S. (1990) J. Neurosci. 10, 1286–1291.

30. Woolley, C. & McEwen, B.S. (1993) J. Comp. Neurol. 336, 293–306.

31. Weiland, N.G. (1992) Endocrinology 131, 662–668.

32. Horner, C.H. (1993) Prog. Neurobiol. 41, 281–321.

33. Siegel, S.J., Brose, N., Janssen, W.G., Gasic, P., Jahn, R., Heinemann, S. & Morrison, J.H. (1994) Proc. Natl. Acad. Sci USA 91, 564–568.

34. Gazzaley, A.H., Siegel, S.J., Kordower, J.H., Mufson, E.J. & Morrison, J.H. (1996) Proc. Natl. Acad. Sci. USA 93, 3121–3125.

35. Gazzaley, A.H., Weiland, N.G., McEwen, B.S. & Morrison, J.H. (1996) J. Neurosci. 16, 6830–6838.

36. Loy, R., Gerlach, J. & McEwen, B.S. (1988) Dev. Brain Res. 39, 245–251.

37. DonCarlos, L.L., Monroy, E. & Morrell, J.I. (1991) J. Comp. Neurol. 305, 591–612.

38. Simerly, R.B., Chang, C., Muramastsu, M. & Swanson, L.W. (1990) J. Comp. Neurol. 29, 76–95.

39. Shughrue, P.J. & Merchenthaler, I. (2000) Neuroscience 99, 605–612.

40. Murphy, D.D. & Segal, M. (1996) J. Neurosci. 16, 4059–4068.

41. Murphy, D.D. & Segal, M. (1997) Proc. Natl. Acad. Sci. USA 94, 1482–1487.

42. Willeit, M., Praschak-Rieder, N., Neumeister, A., Pirker, W., Asenbaum, S., Vitouch, O., Tauscher, J., Hilger, E., Stastny, J., Brucke, T. & Kasper, S. (2000) Biol. Psychiatry 47, 482–489.

43. Murphy, D.D., Cole, N.B. & Segal, M. (1998) Proc. Natl. Acad. Sci. USA 95, 11412–11417.

44. Vicario-Abejon, C., Collin, C., McKay, R.D.G. & Segal, M. (1998) J. Neurosci 18, 7256–7271.

45. Toran-Allerand, C.D., Singh, M. & Setalo, G., Jr. (1999) Front. Neuroendocrinol. 20, 97–121.

46. Razandi, M., Pedram, A., Greene, G.L. & Levin, E.R. (1999) Mol. Endocrinol. 13, 307–319.

47. Clarke, C.H., Norfleet, A.M., Clarke, M.S.F., Watson, C.S., Cunningham, K.A. & Thomas, M.L. (2000) Neuroendocrinology 71, 34–42.

48. Blaustein, J.D., Lehman, M.N., Turcotte, J.C. & Greene, G. (1992) Endocrinology 131, 281–290.

49. Nixon, R.L., Janowsky, D.S. & Davis, J.M. (1979) Res. Commun. Chem. Pathol. Pharmacol. 7, 233–236.

50. Packard, M.G., Kohlmaier, J.R. & Alexander, G.M. (1996) Behav. Neurosci. 110, 626–632.

51. Becker, J.B. (1990) Synapse 5, 157–164.

52. O’Malley, C.A., Hautamaki, M., Kelley, M. & Meyer, E.M. (1987) Brain Res. 403, 389–392.

53. Singh, M., Meyer, E.M., Millard, W.J. & Simpkins, J.W. (1994) Brain Res. 644, 305–312.

54. Peters, A., Palay, S.L. & Webster, H.D. (1991) The Fine Structure of the Nervous System (Oxford Univ. Press, New York), 3rd Ed.

55. Steward, O. & Falk, P.M. (1991) J. Comp. Neurol. 314, 545–557.

56. Murphy, D.D., Cole, N.B., Greenberger, V. & Segal, M. (1998) J. Neurosci. 18, 2550–2559.

57. Rudick, C.N. & Woolley, C.S. (2000) Hippocampus 10, 274–283.

58. Datta, S.R., Brunet, A. & Greenberg, M.E. (1999) Genes Dev. 13, 2905–2927.

59. Du, K.I. & Montminy, M. (1998) J. Biol. Chem. 273, 32377–32379.

60. Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y. & Greer, M.E. (1997) Cell 91, 231–241.

61. Rao, A. & Levi, S. (2000) Neuron 27, 3–5.

62. Friedman, H.V., Bresler, T., Garner, C.C. & Ziv, N.E. (2000) Neuron 27, 57–69.

63. Ziv, N.E. & Smith, S.J. (1996) Neuron 17, 91–102.

64. Smith, S.J. (1999) Science 283, 1860–1861.

65. Craig, A.M., Blackstone, C.D., Huganir, R.L. & Banker, G. (1994) Proc. Natl. Acad. Sci. USA 91, 12373–12377.

66. Brose, N. (1999) Naturwissenschaften 86, 516–524.

67. Carlin, R.K. & Siekevitz, P. (1983) Proc. Natl. Acad. Sci USA 80, 3517–3521.

68. Segal, M., Korkotian, E. & Murphy, D.D. (2000) Trends Neurosci. 23, 53–57.

69. Fong, D.K. & Craig, A.M. (1999) Neuron 23, 195–197.

70. O’Brien, R.J., Xu, D., Petralia, R.S., Steward, O., Huganir, R.L. & Worley, P. (1999) Neuron 23, 309–323.

71. Guzowski, J.F., McNaughton, B.L., Barnes, C.A. & Worley, P.F. (1999) Nat. Neurosci. 2, 1120–1124.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement