Cholesterol's role in synapse formation.

Abstract

A FACTOR RELEASED FROM GLIAL CELLS IN the central nervous system had been known to promote the formation of synapses. That factor, Daniela H. Mauch and colleagues have discovered, is cholesterol (Reports, 9 Nov., p. [1354][1]). In their Perspective accompanying the report by Mauch et al ., Ben A. Barres and Stephen J. Smith begin the final paragraph by asking the question, “Could the cholesterol supply also regulate synaptic plasticity in the adult brain?” ( Science 's Compass, “Cholesterol—making or breaking the synapse,” 9 Nov., p. [1296][2]). In fact, we addressed this issue in a recent paper ([1][3]). We experimentally modeled neuronal cholesterol disbalance by biochemically increasing the turnover of cholesterol in rat hippocampal slices. Such an experimental setup impairs the redistribution of cholesterol from one cell to another via lipoprotein transport. While increasing cholesterol removal, or immediately thereafter, we evoked and recorded two brain waveforms, paired pulse facilitation (PPF) or long-term potentiation (LTP), which are indicative of neurotransmission and synaptic plasticity, respectively. We found that the lack of cholesterol supply to neurons by means of lipoprotein transport impaired PPF and LTP and caused the failure of the neurotransmission and synaptic plasticity. From additional immunofluorescent analysis of the slices, we discovered that cholesterol disbalance also caused neurodegeneration of hippocampal neuronal cell processes and the appearance of tau protein pathology (one of the key features of Alzheimer's disease) in axon fibers of the hippocampus (also called “mossy fibers”). This finding is in accord with other data on cholesterol and tau phosphorylation obtained in neuronal cell culture experiments ([2][4]). 1. [↵][5]1. A. R. Koudinov, 2. N. V. Koudinova , FASEB J. 15, 1858 (2001). [OpenUrl][6][FREE Full Text][7] 2. [↵][8]1. Q. W. Fan, 2. W. Yu, 3. T. Senda, 4. K. Yanagisawa, 5. M. Michikawa , J. Neurochem. 76, 391 (2001). [OpenUrl][9][CrossRef][10][PubMed][11][Web of Science][12] [1]: /lookup/doi/10.1126/science.294.5545.1354 [2]: /lookup/doi/10.1126/science.1066724 [3]: #ref-1 [4]: #ref-2 [5]: #xref-ref-1-1 View reference 1 in text [6]: {openurl}?query=rft.jtitle%253DFASEB%2BJ.%26rft_id%253Dinfo%253Adoi%252F10.1096%252Ffj.00-0815fje%26rft_id%253Dinfo%253Apmid%252F11481254%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [7]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZmFzZWJqIjtzOjU6InJlc2lkIjtzOjEwOiIxNS8xMC8xODU4IjtzOjQ6ImF0b20iO3M6MjU6Ii9zY2kvMjk1LzU1NjMvMjIxMy4xLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [8]: #xref-ref-2-1 View reference 2 in text [9]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2Bneurochemistry%26rft.stitle%253DJ%2BNeurochem%26rft.aulast%253DFan%26rft.auinit1%253DQ.-W.%26rft.volume%253D76%26rft.issue%253D2%26rft.spage%253D391%26rft.epage%253D400%26rft.atitle%253DCholesterol-dependent%2Bmodulation%2Bof%2Btau%2Bphosphorylation%2Bin%2Bcultured%2Bneurons%26rft_id%253Dinfo%253Adoi%252F10.1046%252Fj.1471-4159.2001.00063.x%26rft_id%253Dinfo%253Apmid%252F11208902%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [10]: /lookup/external-ref?access_num=10.1046/j.1471-4159.2001.00063.x&link_type=DOI [11]: /lookup/external-ref?access_num=11208902&link_type=MED&atom=%2Fsci%2F295%2F5563%2F2213.1.atom [12]: /lookup/external-ref?access_num=000166458200008&link_type=ISI