Abstract
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.
Highlights
New neurons incorporate in the granular layer of the dentate gyrus (DG) of the hippocampus throughout life [1]
Our results show that reduced PS1 expression in neural progenitor cells (NPCs) and new neurons causes impairments in pattern separation and novel object recognition (NOR)
To examine whether the function of new neurons in hippocampal learning and memory is PS1-dependent, lentivirus vectors expressing either control shRNA or PS1 shRNA were injected into the subgranular layer (SGL) of the DG
Summary
New neurons incorporate in the granular layer of the dentate gyrus (DG) of the hippocampus throughout life [1]. New neurons in the adult hippocampus are thought to play a role in forms of learning and memory. Whether deficits in neurogenesis play a role in cognitive dysfunction is not clear. This is partially due to the difficulty to discriminate between the role of younger and older neurons. Unraveling the role of neurogenesis in hippocampal function will contribute greatly to the understanding of memory formation. It will provide insight into mechanisms of PLOS ONE | DOI:10.1371/journal.pone.0131266. It will provide insight into mechanisms of PLOS ONE | DOI:10.1371/journal.pone.0131266 June 22, 2015
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