Skip to main content
NCBI home page
Journal of Anatomy logoLink to Journal of Anatomy
. 2000 Nov;197(Pt 4):563–569. doi: 10.1046/j.1469-7580.2000.19740563.x

Parameters of calcium homeostasis in normal neuronal ageing

EMIL C TOESCU 1 , ALEXEJ VERKHRATSKY 2 ,✉
PMCID: PMC1468171  PMID: 11197529

Abstract

The last decade has witnessed a significant turn in our understanding of the mechanisms responsible for the decline of cognitive functions in aged brain. As has been demonstrated by detailed morphological reassessments, the senescence-related changes in cognition cannot be attributed to a simple decrease in the number of neurons. It is becoming clearer that a major cause of age-induced deterioration of brain capability involves much subtler changes at the level of synapses. These changes are either morphological, i.e. reduction in the number of effective synapses and/or functional alterations, i.e. changes in the efficacy of remaining synapses. Important questions are now raised regarding the mechanisms which mediate these synaptic changes. Clearly, an important candidate is calcium, the cytotoxic role of which is already firmly established. The wealth of evidence collected so far regarding the changes of Ca2+ homeostasis in aged neurons shows that the overall duration of cytoplasmic Ca2+ signals becomes longer. This is the most consistent result, demonstrated on different preparations and using different techniques. What is not yet clear is the underlying mechanism, as this result could be explained either through an increased Ca2+ influx or because of a deficit in the Ca2+ buffering/clearance systems. It is conceivable that these prolonged Ca2+ signals may exert a local excitotoxic effect, removing preferentially the most active synapses. Uncovering of the role of Ca2+ in the synaptic function of the aged brain presents an exciting challenge for all those involved in the neurobiology of the senescent CNS.

Keywords: Cognition, synaptic efficiency, excitotoxicity

Full Text

The Full Text of this article is available as a PDF (256.1 KB).

Selected References

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

  1. Baimbridge K. G., Celio M. R., Rogers J. H. Calcium-binding proteins in the nervous system. Trends Neurosci. 1992 Aug;15(8):303–308. doi: 10.1016/0166-2236(92)90081-i. [DOI] [PubMed] [Google Scholar]
  2. Barnes C. A. Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends Neurosci. 1994 Jan;17(1):13–18. doi: 10.1016/0166-2236(94)90029-9. [DOI] [PubMed] [Google Scholar]
  3. Catterall W. A. Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium. 1998 Nov-Dec;24(5-6):307–323. doi: 10.1016/s0143-4160(98)90055-0. [DOI] [PubMed] [Google Scholar]
  4. Choi D. W. Calcium and excitotoxic neuronal injury. Ann N Y Acad Sci. 1994 Dec 15;747:162–171. doi: 10.1111/j.1749-6632.1994.tb44407.x. [DOI] [PubMed] [Google Scholar]
  5. Cowen T., Jenner C., Song G. X., Santoso A. W., Gavazzi I. Responses of mature and aged sympathetic neurons to laminin and NGF: an in vitro study. Neurochem Res. 1997 Aug;22(8):1003–1011. doi: 10.1023/a:1022478926949. [DOI] [PubMed] [Google Scholar]
  6. Duckles S. P., Tsai H., Buchholz J. N. Evidence for decline in intracellular calcium buffering in adrenergic nerves of aged rats. Life Sci. 1996;58(22):2029–2035. doi: 10.1016/0024-3205(96)00194-4. [DOI] [PubMed] [Google Scholar]
  7. Furuichi T., Mikoshiba K. Inositol 1, 4, 5-trisphosphate receptor-mediated Ca2+ signaling in the brain. J Neurochem. 1995 Mar;64(3):953–960. doi: 10.1046/j.1471-4159.1995.64030953.x. [DOI] [PubMed] [Google Scholar]
  8. Geinisman Y., Detoledo-Morrell L., Morrell F., Heller R. E. Hippocampal markers of age-related memory dysfunction: behavioral, electrophysiological and morphological perspectives. Prog Neurobiol. 1995 Feb;45(3):223–252. doi: 10.1016/0301-0082(94)00047-l. [DOI] [PubMed] [Google Scholar]
  9. Ghosh A., Greenberg M. E. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science. 1995 Apr 14;268(5208):239–247. doi: 10.1126/science.7716515. [DOI] [PubMed] [Google Scholar]
  10. Giovannelli L., Pepeu G. Effect of age on K+-induced cytosolic Ca2+ changes in rat cortical synaptosomes. J Neurochem. 1989 Aug;53(2):392–398. doi: 10.1111/j.1471-4159.1989.tb07347.x. [DOI] [PubMed] [Google Scholar]
  11. Gómez-Isla T., Price J. L., McKeel D. W., Jr, Morris J. C., Growdon J. H., Hyman B. T. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci. 1996 Jul 15;16(14):4491–4500. doi: 10.1523/JNEUROSCI.16-14-04491.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hofmann F., Biel M., Flockerzi V. Molecular basis for Ca2+ channel diversity. Annu Rev Neurosci. 1994;17:399–418. doi: 10.1146/annurev.ne.17.030194.002151. [DOI] [PubMed] [Google Scholar]
  13. Hollmann M., Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci. 1994;17:31–108. doi: 10.1146/annurev.ne.17.030194.000335. [DOI] [PubMed] [Google Scholar]
  14. Ichas F., Mazat J. P. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta. 1998 Aug 10;1366(1-2):33–50. doi: 10.1016/s0005-2728(98)00119-4. [DOI] [PubMed] [Google Scholar]
  15. Igwe O. J., Ning L. Inositol 1,4,5-trisphosphate arm of the phosphatidylinositide signal transduction pathway in the rat cerebellum during aging. Neurosci Lett. 1993 Dec 24;164(1-2):167–170. doi: 10.1016/0304-3940(93)90883-m. [DOI] [PubMed] [Google Scholar]
  16. Khachaturian Z. S. Calcium and the aging brain: upsetting a delicate balance? Geriatrics. 1991 Nov;46(11):78-9, 83. [PubMed] [Google Scholar]
  17. Khachaturian Z. S. Calcium hypothesis of Alzheimer's disease and brain aging. Ann N Y Acad Sci. 1994 Dec 15;747:1–11. doi: 10.1111/j.1749-6632.1994.tb44398.x. [DOI] [PubMed] [Google Scholar]
  18. Khachaturian Z. S. Calcium, membranes, aging, and Alzheimer's disease. Introduction and overview. Ann N Y Acad Sci. 1989;568:1–4. doi: 10.1111/j.1749-6632.1989.tb12485.x. [DOI] [PubMed] [Google Scholar]
  19. Kirischuk S., Pronchuk N., Verkhratsky A. Measurements of intracellular calcium in sensory neurons of adult and old rats. Neuroscience. 1992 Oct;50(4):947–951. doi: 10.1016/0306-4522(92)90217-p. [DOI] [PubMed] [Google Scholar]
  20. Kirischuk S., Verkhratsky A. Calcium homeostasis in aged neurones. Life Sci. 1996;59(5-6):451–459. doi: 10.1016/0024-3205(96)00324-4. [DOI] [PubMed] [Google Scholar]
  21. Kirischuk S., Voitenko N., Kostyuk P., Verkhratsky A. Age-associated changes of cytoplasmic calcium homeostasis in cerebellar granule neurons in situ: investigation on thin cerebellar slices. Exp Gerontol. 1996 Jul-Aug;31(4):475–487. doi: 10.1016/0531-5565(95)02070-5. [DOI] [PubMed] [Google Scholar]
  22. Kostyuk P., Pronchuk N., Savchenko A., Verkhratsky A. Calcium currents in aged rat dorsal root ganglion neurones. J Physiol. 1993 Feb;461:467–483. doi: 10.1113/jphysiol.1993.sp019523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Landfield P. W., Pitler T. A. Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science. 1984 Nov 30;226(4678):1089–1092. doi: 10.1126/science.6494926. [DOI] [PubMed] [Google Scholar]
  24. Martinez A., Vitórica J., Satrústegui J. Cytosolic free calcium levels increase with age in rat brain synaptosomes. Neurosci Lett. 1988 Jun 7;88(3):336–342. doi: 10.1016/0304-3940(88)90234-0. [DOI] [PubMed] [Google Scholar]
  25. Martini A., Battaini F., Govoni S., Volpe P. Inositol 1,4,5-trisphosphate receptor and ryanodine receptor in the aging brain of Wistar rats. Neurobiol Aging. 1994 Mar-Apr;15(2):203–206. doi: 10.1016/0197-4580(94)90113-9. [DOI] [PubMed] [Google Scholar]
  26. Michaelis M. L., Bigelow D. J., Schöneich C., Williams T. D., Ramonda L., Yin D., Hühmer A. F., Yao Y., Gao J., Squier T. C. Decreased plasma membrane calcium transport activity in aging brain. Life Sci. 1996;59(5-6):405–412. doi: 10.1016/0024-3205(96)00319-0. [DOI] [PubMed] [Google Scholar]
  27. Murchison D., Griffith W. H. High-voltage-activated calcium currents in basal forebrain neurons during aging. J Neurophysiol. 1996 Jul;76(1):158–174. doi: 10.1152/jn.1996.76.1.158. [DOI] [PubMed] [Google Scholar]
  28. Murchison D., Griffith W. H. Low-voltage activated calcium currents increase in basal forebrain neurons from aged rats. J Neurophysiol. 1995 Aug;74(2):876–887. doi: 10.1152/jn.1995.74.2.876. [DOI] [PubMed] [Google Scholar]
  29. Pagliusi S. R., Gerrard P., Abdallah M., Talabot D., Catsicas S. Age-related changes in expression of AMPA-selective glutamate receptor subunits: is calcium-permeability altered in hippocampal neurons? Neuroscience. 1994 Aug;61(3):429–433. doi: 10.1016/0306-4522(94)90422-7. [DOI] [PubMed] [Google Scholar]
  30. Pozzan T., Rizzuto R., Volpe P., Meldolesi J. Molecular and cellular physiology of intracellular calcium stores. Physiol Rev. 1994 Jul;74(3):595–636. doi: 10.1152/physrev.1994.74.3.595. [DOI] [PubMed] [Google Scholar]
  31. Satrústegui J., Villalba M., Pereira R., Bogónez E., Martínez-Serrano A. Cytosolic and mitochondrial calcium in synaptosomes during aging. Life Sci. 1996;59(5-6):429–434. doi: 10.1016/0024-3205(96)00322-0. [DOI] [PubMed] [Google Scholar]
  32. Svoboda K., Denk W., Kleinfeld D., Tank D. W. In vivo dendritic calcium dynamics in neocortical pyramidal neurons. Nature. 1997 Jan 9;385(6612):161–165. doi: 10.1038/385161a0. [DOI] [PubMed] [Google Scholar]
  33. Thibault O., Landfield P. W. Increase in single L-type calcium channels in hippocampal neurons during aging. Science. 1996 May 17;272(5264):1017–1020. doi: 10.1126/science.272.5264.1017. [DOI] [PubMed] [Google Scholar]
  34. Thibault O., Porter N. M., Chen K. C., Blalock E. M., Kaminker P. G., Clodfelter G. V., Brewer L. D., Landfield P. W. Calcium dysregulation in neuronal aging and Alzheimer's disease: history and new directions. Cell Calcium. 1998 Nov-Dec;24(5-6):417–433. doi: 10.1016/s0143-4160(98)90064-1. [DOI] [PubMed] [Google Scholar]
  35. Toescu E. C. Apoptosis and cell death in neuronal cells: where does Ca2+ fit in? Cell Calcium. 1998 Nov-Dec;24(5-6):387–403. doi: 10.1016/s0143-4160(98)90062-8. [DOI] [PubMed] [Google Scholar]
  36. Toescu E. C. Intraneuronal Ca2+ stores act mainly as a 'Ca2+ sink' in cerebellar granule neurones. Neuroreport. 1998 Apr 20;9(6):1227–1231. doi: 10.1097/00001756-199804200-00049. [DOI] [PubMed] [Google Scholar]
  37. Verkhratsky A. J., Petersen O. H. Neuronal calcium stores. Cell Calcium. 1998 Nov-Dec;24(5-6):333–343. doi: 10.1016/s0143-4160(98)90057-4. [DOI] [PubMed] [Google Scholar]
  38. Verkhratsky A., Shmigol A. Calcium-induced calcium release in neurones. Cell Calcium. 1996 Jan;19(1):1–14. doi: 10.1016/s0143-4160(96)90009-3. [DOI] [PubMed] [Google Scholar]
  39. Verkhratsky A., Shmigol A., Kirischuk S., Pronchuk N., Kostyuk P. Age-dependent changes in calcium currents and calcium homeostasis in mammalian neurons. Ann N Y Acad Sci. 1994 Dec 15;747:365–381. doi: 10.1111/j.1749-6632.1994.tb44423.x. [DOI] [PubMed] [Google Scholar]
  40. Verkhratsky A., Toescu E. C. Calcium and neuronal ageing. Trends Neurosci. 1998 Jan;21(1):2–7. doi: 10.1016/s0166-2236(97)01156-9. [DOI] [PubMed] [Google Scholar]
  41. Villa A., Podini P., Panzeri M. C., Racchetti G., Meldolesi J. Cytosolic Ca2+ binding proteins during rat brain ageing: loss of calbindin and calretinin in the hippocampus, with no change in the cerebellum. Eur J Neurosci. 1994 Sep 1;6(9):1491–1499. doi: 10.1111/j.1460-9568.1994.tb01010.x. [DOI] [PubMed] [Google Scholar]
  42. West M. J., Coleman P. D., Flood D. G., Troncoso J. C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet. 1994 Sep 17;344(8925):769–772. doi: 10.1016/s0140-6736(94)92338-8. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Anatomy are provided here courtesy of Anatomical Society of Great Britain and Ireland

RESOURCES