Journal Article

Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory

Kuttner-Hirshler, Yafit, Tobin, Matthew K., Pizzi, Michael, Bonds, Jacqueline A., Marr, Robert, Bartolotti, Nancy, Lazarov, Orly

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aging / Alzheimer's disease / Animals / Aspartic endopeptidase / beta Catenin - physiology / Biology / Catalysis / Cells (biology) / Cognitive ability / Cognitive impairment / 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