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Updated: Apr 28, 2026
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Published on: September 4, 2015
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Synaptic function of nicastrin in hippocampal neurons
Sang Hun Lee1, Manu Sharma2, Thomas C Südhof3
1Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital.
Summary
Nicastrin, a key component of gamma-secretase, is crucial for synaptic plasticity in Alzheimer's disease (AD) research. Its absence impairs neuronal communication and calcium homeostasis, impacting brain function.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Synaptic dysfunction is a hallmark of Alzheimer's disease (AD) pathogenesis.
- Presenilins are implicated in familial AD and are vital for synaptic plasticity and neuronal survival.
- The role of nicastrin, a gamma-secretase component, in central synaptic function remains unclear.
Purpose of the Study:
- To investigate the role of nicastrin in synaptic function and plasticity.
- To determine if nicastrin regulates synaptic function in a gamma-secretase-dependent or independent manner.
- To elucidate the impact of nicastrin depletion on synaptic plasticity in the hippocampus.
Main Methods:
- Utilized nicastrin conditional knockout (cKO) mice.
- Employed electrophysiological recordings in the hippocampal Schaffer collateral pathway.
- Analyzed presynaptic short-term plasticity, NMDA receptor-mediated responses, and long-term potentiation.
Main Results:
- Nicastrin deletion led to deficits in presynaptic short-term plasticity (paired-pulse and frequency facilitation).
- Disrupted intracellular calcium (Ca2+) homeostasis underlies these presynaptic deficits.
- Impaired NMDA receptor responses and long-term potentiation were observed in older nicastrin cKO mice.
Conclusions:
- Nicastrin is essential for both short- and long-term synaptic plasticity in mature neurons.
- These findings highlight the critical role of gamma-secretase components in maintaining synaptic function.
- Nicastrin's involvement in synaptic regulation underscores its importance in neurological health and potentially AD.
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