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Presenilins are essential for regulating neurotransmitter release

Abstract

Mutations in the presenilin genes are the main cause of familial Alzheimer’s disease. Loss of presenilin activity and/or accumulation of amyloid-β peptides have been proposed to mediate the pathogenesis of Alzheimer’s disease by impairing synaptic function1,2,3,4,5. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we use a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We show that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, we found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-d-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca2+ stores by thapsigargin, or blockade of Ca2+ release from these stores by ryanodine receptor inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Collectively, these results indicate a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca2+ release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer’s disease.

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Figure 1: Impaired LTP in CA3- Psen but not CA1- Psen cDKO mice.
Figure 2: Presynaptic defects in CA3- Psen but not CA1- Psen cDKO mice.
Figure 3: Presynaptic presenilin regulates glutamate release by intracellular Ca 2+ stores.
Figure 4: Blockade of RyRs mimics and occludes the defects in synaptic facilitation and calcium homeostasis in CA3- Psen cDKO hippocampal slices and cultured Psen cDKO hippocampal neurons.

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References

  1. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Hsia, A. Y. et al. Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl Acad. Sci. USA 96, 3228–3233 (1999)

    Article  ADS  CAS  Google Scholar 

  3. Saura, C. A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36 (2004)

    Article  CAS  Google Scholar 

  4. Selkoe, D. J. Alzheimer’s disease is a synaptic failure. Science 298, 789–791 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Shen, J. & Kelleher, R. J. The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl Acad. Sci. USA 104, 403–409 (2007)

    Article  ADS  CAS  Google Scholar 

  6. Feng, R. et al. Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer’s presenilin-1 and presenilin-2. Proc. Natl Acad. Sci. USA 101, 8162–8167 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Zakharenko, S. S. et al. Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1–CA3 synapses. Neuron 39, 975–990 (2003)

    Article  CAS  Google Scholar 

  8. Nakazawa, K. et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297, 211–218 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Yu, H. et al. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 31, 713–726 (2001)

    Article  CAS  Google Scholar 

  10. Hessler, N. A., Shirke, A. M. & Malinow, R. The probability of transmitter release at a mammalian central synapse. Nature 366, 569–572 (1993)

    Article  ADS  CAS  Google Scholar 

  11. Rosenmund, C., Clements, J. D. & Westbrook, G. L. Nonuniform probability of glutamate release at a hippocampal synapse. Science 262, 754–757 (1993)

    Article  ADS  CAS  Google Scholar 

  12. Emptage, N. J., Reid, C. A. & Fine, A. Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release. Neuron 29, 197–208 (2001)

    Article  CAS  Google Scholar 

  13. Chan, S. L., Mayne, M., Holden, C. P., Geiger, J. D. & Mattson, M. P. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J. Biol. Chem. 275, 18195–18200 (2000)

    Article  CAS  Google Scholar 

  14. Green, K. N. et al. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J. Cell Biol. 181, 1107–1116 (2008)

    Article  CAS  Google Scholar 

  15. Stutzmann, G. E., Caccamo, A., LaFerla, F. M. & Parker, I. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J. Neurosci. 24, 508–513 (2004)

    Article  CAS  Google Scholar 

  16. Tu, H. et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126, 981–993 (2006)

    Article  CAS  Google Scholar 

  17. Treiman, M., Caspersen, C. & Christensen, S. B. A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases. Trends Pharmacol. Sci. 19, 131–135 (1998)

    Article  CAS  Google Scholar 

  18. Gafni, J. et al. Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor. Neuron 19, 723–733 (1997)

    Article  CAS  Google Scholar 

  19. Meissner, G. Ryanodine activation and inhibition of the Ca2+ release channel of sarcoplasmic reticulum. J. Biol. Chem. 261, 6300–6306 (1986)

    CAS  PubMed  Google Scholar 

  20. Stutzmann, G. E. et al. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J. Neurosci. 26, 5180–5189 (2006)

    Article  CAS  Google Scholar 

  21. Handler, M., Yang, X. & Shen, J. Presenilin-1 regulates neuronal differentiation during neurogenesis. Development 127, 2593–2606 (2000)

    CAS  PubMed  Google Scholar 

  22. Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 (1997)

    Article  CAS  Google Scholar 

  23. Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003)

    Article  CAS  Google Scholar 

  24. Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci. 8, 1051–1058 (2005)

    Article  CAS  Google Scholar 

  25. Buxbaum, J. D. et al. Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J. Neurosci. 18, 9629–9637 (1998)

    Article  CAS  Google Scholar 

  26. Lazarov, O., Lee, M., Peterson, D. A. & Sisodia, S. S. Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J. Neurosci. 22, 9785–9793 (2002)

    Article  CAS  Google Scholar 

  27. Yao, P. J. & Coleman, P. D. Reduced O-glycosylated clathrin assembly protein AP180: implication for synaptic vesicle recycling dysfunction in Alzheimer’s disease. Neurosci. Lett. 252, 33–36 (1998)

    Article  CAS  Google Scholar 

  28. Saura, C. A. et al. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J. Neurosci. 25, 6755–6764 (2005)

    Article  CAS  Google Scholar 

  29. Goldberg, M. S. et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45, 489–496 (2005)

    Article  CAS  Google Scholar 

  30. Kitada, T. et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc. Natl Acad. Sci. USA 104, 11441–11446 (2007)

    Article  ADS  CAS  Google Scholar 

  31. Steiner, H. et al. A loss of function mutation of presenilin-2 interferes with amyloid β-peptide production and notch signaling. J. Biol. Chem. 274, 28669–28673 (1999)

    Article  CAS  Google Scholar 

  32. Wines-Samuelson, M., Handler, M. & Shen, J. Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons. Dev. Biol. 277, 332–346 (2005)

    Article  CAS  Google Scholar 

  33. Watanabe, H. et al. Indirect regulation of presenilins in CREB-mediated transcription. J. Biol. Chem. 284, 13705–13713 (2009)

    Article  CAS  Google Scholar 

  34. Zhang, C. & Zhou, Z. Ca2+-independent but voltage-dependent secretion in mammalian dorsal root ganglion neurons. Nature Neurosci. 5, 425–430 (2002)

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank K. Nakazawa and S. Tonegawa for Grik4-Cre transgenic mice, R. Kelleher for discussions and comments, and X. Zou for technical assistance. This work was supported by a grant from the National Institutes of Health (NIH; R01NS041783 to J.S.).

Author Contributions C.Z., B.W., V.B. and M.W.S. performed experiments and contributed to figures; D.Z. performed experiments; I.D. provided reagents; C.Z., B.W., T.C.S. and J.S. designed the research and wrote the paper.

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Correspondence to Jie Shen.

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Zhang, C., Wu, B., Beglopoulos, V. et al. Presenilins are essential for regulating neurotransmitter release. Nature 460, 632–636 (2009). https://doi.org/10.1038/nature08177

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