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Presenilins are essential for regulating neurotransmitter release.

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Title: Presenilins are essential for regulating neurotransmitter release.
Authors: Chen Zhang, Bei Wu, Beglopoulos, Vassilios, Wines-Samuelson, Mary, Dawei Zhang, Dragatsis, Ioannis, Südhof, Thomas C., Jie Shen
Source: Nature. 7/30/2009, Vol. 460 Issue 7255, p632-636. 5p. 4 Graphs.
Subjects: Presenilins, Alzheimer's disease, Neural transmission, Membrane proteins, Chromosome abnormalities, Mutagenesis, Synapses, Neural circuitry, Neurotransmitters, Genetic disorders
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 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 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. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: <searchLink fieldCode="AR" term="%22Chen+Zhang%22">Chen Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Bei+Wu%22">Bei Wu</searchLink><br /><searchLink fieldCode="AR" term="%22Beglopoulos%2C+Vassilios%22">Beglopoulos, Vassilios</searchLink><br /><searchLink fieldCode="AR" term="%22Wines-Samuelson%2C+Mary%22">Wines-Samuelson, Mary</searchLink><br /><searchLink fieldCode="AR" term="%22Dawei+Zhang%22">Dawei Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Dragatsis%2C+Ioannis%22">Dragatsis, Ioannis</searchLink><br /><searchLink fieldCode="AR" term="%22Südhof%2C+Thomas+C%2E%22">Südhof, Thomas C.</searchLink><br /><searchLink fieldCode="AR" term="%22Jie+Shen%22">Jie Shen</searchLink>
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  Data: 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 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 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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              Text: 7/30/2009
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