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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

Compromised survival of new neurons expressing reduced levels of PS1 in the granular cell layer of the dentate gyrus of adult mice.Unbiased stereological analysis of green fluorescent protein positive (GFP+) cell populations in the SGL and GCL of the DG at 3 and 6 months post-injection. A. Less mature neurons within the GCL (GFP+BrdU-NeuN+; *P<0.05) of mice injected with PS1 shRNA. B. Separate Comparisons within RL and PS1 groups at 3 and 6 months post injection reveals reduced survival of new neurons in the GCL of PS1 shRNA (GFP+BrdU+NeuN+; *P<0.05). Error bars indicate ±SEM. C. Confocal image (Zeiss LSM 510) representing colocalization of GFP with NeuN and BrdU (63x). (D,E). Comparisons within RL and PS1 groups at 3 and 6 months post injection shows reduced rate of survival of PDGFRα+ NPCs in the SGL (GFP+PDGFRα+Nestin-; **P<0.01) (D) and of total neurons and oligodendrocytes within the SGL (GFP+PDGFRα+; **P<0.01), (E). Error bars indicate ±SEM. F. Confocal image (Zeiss LSM 510) representing colocalization of GFP, nestin and PDGFRα (63x).
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pone.0131266.g004: Compromised survival of new neurons expressing reduced levels of PS1 in the granular cell layer of the dentate gyrus of adult mice.Unbiased stereological analysis of green fluorescent protein positive (GFP+) cell populations in the SGL and GCL of the DG at 3 and 6 months post-injection. A. Less mature neurons within the GCL (GFP+BrdU-NeuN+; *P<0.05) of mice injected with PS1 shRNA. B. Separate Comparisons within RL and PS1 groups at 3 and 6 months post injection reveals reduced survival of new neurons in the GCL of PS1 shRNA (GFP+BrdU+NeuN+; *P<0.05). Error bars indicate ±SEM. C. Confocal image (Zeiss LSM 510) representing colocalization of GFP with NeuN and BrdU (63x). (D,E). Comparisons within RL and PS1 groups at 3 and 6 months post injection shows reduced rate of survival of PDGFRα+ NPCs in the SGL (GFP+PDGFRα+Nestin-; **P<0.01) (D) and of total neurons and oligodendrocytes within the SGL (GFP+PDGFRα+; **P<0.01), (E). Error bars indicate ±SEM. F. Confocal image (Zeiss LSM 510) representing colocalization of GFP, nestin and PDGFRα (63x).

Mentions: To elucidate the mechanism by which reduction in PS1 expression in NPCs and new neurons compromises hippocampal function, we examined the effect of PS1 knockdown on the neurogenic lineages in the DG. We previously showed that 6 weeks following lentiviral injection, there are more new neurons in the SGL of mice injected with PS1 shRNA compared to control shRNA [13]. Thus, we first examined whether this increase is sustained 3 and 6 months post injection. We observed no difference in the number of neuroblasts or immature neurons in the SGL of the two groups 3 and 6 months post infection (S1 Fig 1ai-iii). This may suggest that either their rate of survival is compromised or that the increase in differentiating NPCs is transient. To address the former, we examined the number of new neurons in the GCL. Indeed, we observed that the number of mature neurons in the GCL of mice injected with PS1 shRNA is significantly reduced 3 months post injection (Fig 4a). To verify that their rate of survival is compromised, we compared the number of new neurons in the GCL at 3 months with their number at 6 months. We found that in the control injected mice, there was a reduction in the number of surviving new neurons in the GCL, albeit not statistically significant (Fig 4b and 4c). In contrast, there was a significant reduction in the number of surviving new neurons in the PS1 shRNA group (Fig 4b, *P<0.05). To examine whether NPCs exhibit reduced rate of survival when PS1 is downregulated, we went back and examined the number of surviving NPCs in the SGL at 3 and 6 months post injection in each one of the groups. Indeed, significantly less NPCs (PDGFRα expressing progenitors that give rise to oligodendrocytes or neurons) survived in the SGL of the PS1 shRNA compared to control mice (Fig 4d and 4f, *P<0.05). Likewise, a significant drop in the survival of mature neurons and oligodendrocytes expressing PDGFRα was observed between the 3 and 6 month time points in the PS1 shRNA mice (Fig 4e, *P<0.05). Further analysis revealed no effect on the number of neural stem cells or mature astrocytes (S1 Fig 1bi-iii). Taken together, these results suggest that downregulation of PS1 in NPCs compromises their survival, as well as the survival of new neurons, leading to reduced number of new neurons in the GCL.


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)

Compromised survival of new neurons expressing reduced levels of PS1 in the granular cell layer of the dentate gyrus of adult mice.Unbiased stereological analysis of green fluorescent protein positive (GFP+) cell populations in the SGL and GCL of the DG at 3 and 6 months post-injection. A. Less mature neurons within the GCL (GFP+BrdU-NeuN+; *P<0.05) of mice injected with PS1 shRNA. B. Separate Comparisons within RL and PS1 groups at 3 and 6 months post injection reveals reduced survival of new neurons in the GCL of PS1 shRNA (GFP+BrdU+NeuN+; *P<0.05). Error bars indicate ±SEM. C. Confocal image (Zeiss LSM 510) representing colocalization of GFP with NeuN and BrdU (63x). (D,E). Comparisons within RL and PS1 groups at 3 and 6 months post injection shows reduced rate of survival of PDGFRα+ NPCs in the SGL (GFP+PDGFRα+Nestin-; **P<0.01) (D) and of total neurons and oligodendrocytes within the SGL (GFP+PDGFRα+; **P<0.01), (E). Error bars indicate ±SEM. F. Confocal image (Zeiss LSM 510) representing colocalization of GFP, nestin and PDGFRα (63x).
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pone.0131266.g004: Compromised survival of new neurons expressing reduced levels of PS1 in the granular cell layer of the dentate gyrus of adult mice.Unbiased stereological analysis of green fluorescent protein positive (GFP+) cell populations in the SGL and GCL of the DG at 3 and 6 months post-injection. A. Less mature neurons within the GCL (GFP+BrdU-NeuN+; *P<0.05) of mice injected with PS1 shRNA. B. Separate Comparisons within RL and PS1 groups at 3 and 6 months post injection reveals reduced survival of new neurons in the GCL of PS1 shRNA (GFP+BrdU+NeuN+; *P<0.05). Error bars indicate ±SEM. C. Confocal image (Zeiss LSM 510) representing colocalization of GFP with NeuN and BrdU (63x). (D,E). Comparisons within RL and PS1 groups at 3 and 6 months post injection shows reduced rate of survival of PDGFRα+ NPCs in the SGL (GFP+PDGFRα+Nestin-; **P<0.01) (D) and of total neurons and oligodendrocytes within the SGL (GFP+PDGFRα+; **P<0.01), (E). Error bars indicate ±SEM. F. Confocal image (Zeiss LSM 510) representing colocalization of GFP, nestin and PDGFRα (63x).
Mentions: To elucidate the mechanism by which reduction in PS1 expression in NPCs and new neurons compromises hippocampal function, we examined the effect of PS1 knockdown on the neurogenic lineages in the DG. We previously showed that 6 weeks following lentiviral injection, there are more new neurons in the SGL of mice injected with PS1 shRNA compared to control shRNA [13]. Thus, we first examined whether this increase is sustained 3 and 6 months post injection. We observed no difference in the number of neuroblasts or immature neurons in the SGL of the two groups 3 and 6 months post infection (S1 Fig 1ai-iii). This may suggest that either their rate of survival is compromised or that the increase in differentiating NPCs is transient. To address the former, we examined the number of new neurons in the GCL. Indeed, we observed that the number of mature neurons in the GCL of mice injected with PS1 shRNA is significantly reduced 3 months post injection (Fig 4a). To verify that their rate of survival is compromised, we compared the number of new neurons in the GCL at 3 months with their number at 6 months. We found that in the control injected mice, there was a reduction in the number of surviving new neurons in the GCL, albeit not statistically significant (Fig 4b and 4c). In contrast, there was a significant reduction in the number of surviving new neurons in the PS1 shRNA group (Fig 4b, *P<0.05). To examine whether NPCs exhibit reduced rate of survival when PS1 is downregulated, we went back and examined the number of surviving NPCs in the SGL at 3 and 6 months post injection in each one of the groups. Indeed, significantly less NPCs (PDGFRα expressing progenitors that give rise to oligodendrocytes or neurons) survived in the SGL of the PS1 shRNA compared to control mice (Fig 4d and 4f, *P<0.05). Likewise, a significant drop in the survival of mature neurons and oligodendrocytes expressing PDGFRα was observed between the 3 and 6 month time points in the PS1 shRNA mice (Fig 4e, *P<0.05). Further analysis revealed no effect on the number of neural stem cells or mature astrocytes (S1 Fig 1bi-iii). Taken together, these results suggest that downregulation of PS1 in NPCs compromises their survival, as well as the survival of new neurons, leading to reduced number of new neurons in the GCL.

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