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Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory.

Bonds JA, Kuttner-Hirshler Y, Bartolotti N, Tobin MK, Pizzi M, Marr R, Lazarov O - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America; Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Impairments in novel object recognition at 3 and 6 months after PS1 knockdown in neural progenitor cells.Percentage of time spent exploring the novel or familiar object by mice injected with either the control RL shRNA or PS1 shRNA at 3 (A) and 6 months (B). In contrast to RL-injected mice, PS1 shRNA-injected mice show no preference for the novel object at both time-points (unpaired t-test, *p<0.05). Error bars indicate ±SEM.
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pone.0131266.g003: Impairments in novel object recognition at 3 and 6 months after PS1 knockdown in neural progenitor cells.Percentage of time spent exploring the novel or familiar object by mice injected with either the control RL shRNA or PS1 shRNA at 3 (A) and 6 months (B). In contrast to RL-injected mice, PS1 shRNA-injected mice show no preference for the novel object at both time-points (unpaired t-test, *p<0.05). Error bars indicate ±SEM.

Mentions: A common test for the diagnosis of hippocampal amnesia is visual paired comparison task. Novel object recognition (NOR) is the equivalent in rodents. Impairments in NOR have been shown in FAD-linked mouse models [14]. Thus, we attempted to determine whether PS1 knockdown in new neurons has an effect on exploratory preference. We observed that RL shRNA injected mice showed a clear preference for the novel object both 3 and 6 months post injection (Fig 3a and 3b; N = 7, *P<0.05), while the exploratory preference of PS1 shRNA mice was impaired, as manifested by their exploration time (Fig 3a and 3b, N = 8, P>0.05). These results suggest that downregulation of PS1 in NPCs and new neurons, has long-term effects on hippocampal function.


Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory.

Bonds JA, Kuttner-Hirshler Y, Bartolotti N, Tobin MK, Pizzi M, Marr R, Lazarov O - PLoS ONE (2015)

Impairments in novel object recognition at 3 and 6 months after PS1 knockdown in neural progenitor cells.Percentage of time spent exploring the novel or familiar object by mice injected with either the control RL shRNA or PS1 shRNA at 3 (A) and 6 months (B). In contrast to RL-injected mice, PS1 shRNA-injected mice show no preference for the novel object at both time-points (unpaired t-test, *p<0.05). Error bars indicate ±SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4476567&req=5

pone.0131266.g003: Impairments in novel object recognition at 3 and 6 months after PS1 knockdown in neural progenitor cells.Percentage of time spent exploring the novel or familiar object by mice injected with either the control RL shRNA or PS1 shRNA at 3 (A) and 6 months (B). In contrast to RL-injected mice, PS1 shRNA-injected mice show no preference for the novel object at both time-points (unpaired t-test, *p<0.05). Error bars indicate ±SEM.
Mentions: A common test for the diagnosis of hippocampal amnesia is visual paired comparison task. Novel object recognition (NOR) is the equivalent in rodents. Impairments in NOR have been shown in FAD-linked mouse models [14]. Thus, we attempted to determine whether PS1 knockdown in new neurons has an effect on exploratory preference. We observed that RL shRNA injected mice showed a clear preference for the novel object both 3 and 6 months post injection (Fig 3a and 3b; N = 7, *P<0.05), while the exploratory preference of PS1 shRNA mice was impaired, as manifested by their exploration time (Fig 3a and 3b, N = 8, P>0.05). These results suggest that downregulation of PS1 in NPCs and new neurons, has long-term effects on hippocampal function.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America; Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus