Presenilins are essential for regulating neurotransmitter release

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Abstract
The presenilin genes have been genetically associated with familial cases of Alzheimer's disease but where they operate and what they do in neurons has been unclear. Zhang et al. demonstrate in mouse models that presinilins act in the presynaptic compartment to control activity-dependent neurotransmitter release, a process essential to neuronal computation, learning and memory. These findings suggest that presynaptic dysfunction might be an early cause of dementia in neurodegenerative disorders. Mutations in the presenilin genes are associated with familial cases of Alzheimer's disease, but the precise site and nature of the synaptic dysfunction remain unknown. Using a genetic approach to selectively inactivate presenilins in a mouse model, it has been possible to demonstrate that they act in the presynaptic compartment to control the activity-dependent efficacy of neurotransmitter release, a process essential for neuronal computation, learning and memory. 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.