Helen & Robert Appel Alzheimer’s Disease Research Institute

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TitleSynaptic function of nicastrin in hippocampal neurons.
Publication TypeJournal Article
Year of Publication2014
AuthorsLee SHun, Sharma M, Südhof TC, Shen J
JournalProc Natl Acad Sci U S A
Volume111
Issue24
Pagination8973-8
Date Published2014 Jun 17
ISSN1091-6490
KeywordsAlzheimer Disease, Amyloid Precursor Protein Secretases, Animals, Brain, Disease Models, Animal, Hippocampus, Learning, Long-Term Potentiation, Membrane Glycoproteins, Memory, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neuronal Plasticity, Neurons, Presenilins, Receptors, N-Methyl-D-Aspartate, Synapses
Abstract

Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short- and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca(2+) in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca(2+) homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short- and long-term synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.

DOI10.1073/pnas.1408554111
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID24889619
PubMed Central IDPMC4066509
Grant ListR01 NS042818 / NS / NINDS NIH HHS / United States
R01NS042818 / NS / NINDS NIH HHS / United States
R01 NS041783 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 NS041779 / NS / NINDS NIH HHS / United States
R01NS041779 / NS / NINDS NIH HHS / United States