Presenilins are essential for regulating neurotransmitter release

Abstract

SummaryMutations in the presenilin genes are the major cause of familial Alzheimer's disease (AD). Loss of presenilin activity and/or accumulation of amyloid-β peptides have been proposed to mediate the pathogenesis of AD by impairing synaptic function1-5. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we employ a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We found that long-term potentiation (LTP) induced by theta burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, 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 receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Strikingly, 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 reveal a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and LTP induction via 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 AD.