Presenilins are essential for regulating neurotransmitter release

Chen Zhang, Bei Wu, Vassilios Beglopoulos, Mary Wines-Samuelson, Dawei Zhang, Ioannis Dragatsis, Thomas C. Südhof, Jie Shen

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Mutations in the presenilin genes are the main cause of familial Alzheimers disease. Loss of presenilin activity and/or accumulation of amyloid-Β peptides have been proposed to mediate the pathogenesis of Alzheimers disease by impairing synaptic function. 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 Ca 2+ stores by thapsigargin, or blockade of Ca 2+ 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 Ca 2+ release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimers disease.

Original languageEnglish (US)
Pages (from-to)632-636
Number of pages5
JournalNature
Volume460
Issue number7255
DOIs
StatePublished - Jul 30 2009

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Presenilins
Neurotransmitter Agents
Alzheimer Disease
Long-Term Potentiation
Ryanodine Receptor Calcium Release Channel
Neuronal Plasticity
Thapsigargin
Dizocilpine Maleate
Presynaptic Terminals
Amyloid
Endoplasmic Reticulum
Dementia
Glutamic Acid
Neurons
Peptides
Mutation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Zhang, C., Wu, B., Beglopoulos, V., Wines-Samuelson, M., Zhang, D., Dragatsis, I., ... Shen, J. (2009). Presenilins are essential for regulating neurotransmitter release. Nature, 460(7255), 632-636. https://doi.org/10.1038/nature08177

Presenilins are essential for regulating neurotransmitter release. / Zhang, Chen; Wu, Bei; Beglopoulos, Vassilios; Wines-Samuelson, Mary; Zhang, Dawei; Dragatsis, Ioannis; Südhof, Thomas C.; Shen, Jie.

In: Nature, Vol. 460, No. 7255, 30.07.2009, p. 632-636.

Research output: Contribution to journalArticle

Zhang, C, Wu, B, Beglopoulos, V, Wines-Samuelson, M, Zhang, D, Dragatsis, I, Südhof, TC & Shen, J 2009, 'Presenilins are essential for regulating neurotransmitter release', Nature, vol. 460, no. 7255, pp. 632-636. https://doi.org/10.1038/nature08177
Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I et al. Presenilins are essential for regulating neurotransmitter release. Nature. 2009 Jul 30;460(7255):632-636. https://doi.org/10.1038/nature08177
Zhang, Chen ; Wu, Bei ; Beglopoulos, Vassilios ; Wines-Samuelson, Mary ; Zhang, Dawei ; Dragatsis, Ioannis ; Südhof, Thomas C. ; Shen, Jie. / Presenilins are essential for regulating neurotransmitter release. In: Nature. 2009 ; Vol. 460, No. 7255. pp. 632-636.
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