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Paper Chase

Synaptic function of nicastrin in hippocampal neurons.

Proc. Natl. Acad. Sci. U.S.A.. Jun 17, 2014;111(24):8973-8.
Lee SH, Sharma M, Südhof TC, Shen J.

Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital,Program in Neuroscience, Harvard Medical School, Boston, MA 02115; and


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.