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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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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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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DOI: https://doi.org/10.1038/nature08177
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