Editors' ChoiceNeuroscience

Presynaptic Presenilins Promote Potentiation

Science Signaling  04 Aug 2009:
Vol. 2, Issue 82, pp. ec261
DOI: 10.1126/scisignal.282ec261

Presenilins are membrane proteins that constitute part of the γ-secretase complex, which is involved in the cleavage of amyloid precursor protein to form β-amyloid (Aβ) peptides, accumulation of which is associated with Alzheimer’s disease (AD). Mutations in presenilin-encoding genes are associated with synaptic dysfunction and familial AD, but the precise role and site of action of the presenilins in synaptic function is unclear. Zhang et al. generated mice with specific knockout of both presenilin-encoding genes in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampus. Knockout of presynaptic, but not postsynaptic, presenilins impaired long-term potentiation (LTP), but this was not due to defects in neurotransmitter receptor function in the postsynaptic neurons. Instead, paired-pulse facilitation and synaptic frequency facilitation were reduced when presenilins were knocked out in CA3 neurons, effects that were reversed by the addition of extracellular Ca2+. CA3 neurons lacking in presenilins released less glutamate than did CA3 neurons from wild-type (WT) mice. Presenilin-deficient and WT CA3 neurons exhibited similar uptake of extracellular Ca2+ through voltage-gated Ca2+ channels; however, depleting intracellular stores of Ca2+ with thapsigargin blocked synaptic activity in CA3 neurons from WT mice but had no further effect on the already impaired synaptic facilitation of presenilin-deficient CA3 neurons. Inhibition of ryanodine receptors (RyRs), but not IP3 receptors, mimicked the effects of thapsigargin. Cultured, presenilin-deficient hippocampal neurons showed reduced changes in intracellular Ca2+ in response to depolarization compared with those of WT neurons; inhibition of RyRs did not exacerbate this defect. Although the mechanism by which presenilins modulate RyR-mediated release of Ca2+ is unclear, this study suggests that presynaptic presenilins play a critical role in enhancing neurotransmitter release and LTP.

C. Zhang, B. Wu, V. Beglopoulos, M. Wines-Samuelson, D. Zhang, I. Dragatsis, T. C. Südhof, J. Shen, Presenilins are essential for regulating neurotransmitter release. Nature 460, 632–636 (2009).[PubMed]