Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory

Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learni...

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Bibliographic Details
Published in:PloS one 2015-06, Vol.10 (6), p.e0131266-e0131266
Main Authors: Bonds, Jacqueline A, Kuttner-Hirshler, Yafit, Bartolotti, Nancy, Tobin, Matthew K, Pizzi, Michael, Marr, Robert, Lazarov, Orly
Format: Article
Language:English
Subjects:
Aging
Alzheimer's disease
Animals
Aspartic endopeptidase
beta Catenin - physiology
Biology
Catalysis
Cells (biology)
Cognitive ability
Dendritic branching
Dendritic spines
Dentate Gyrus - physiology
Discrimination Learning - physiology
Down-Regulation
Exploration
Gene Knockdown Techniques
Granule cells
Hippocampus
Hippocampus - growth & development
Hippocampus - physiology
Kinases
Learning
Learning - physiology
Male
Medicine
Memory
Memory - physiology
Mice, Inbred C57BL
Neural stem cells
Neural Stem Cells - physiology
Neurogenesis
Neurogenesis - physiology
Neurosciences
Notch protein
Phase transitions
Phosphorylation
Presenilin 1
Presenilin-1 - physiology
Progenitor cells
Proteases
Receptors, Notch - physiology
Rodents
Secretase
Signal Transduction - physiology
Stem cells
β-Catenin
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Summary:Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer's disease.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0131266