Abstract
A delicate balance between quiescence and division of the radial glia-like stem cells (RGLs) ensures continuation of adult hippocampal neurogenesis (AHN) over the lifespan. Transient or persistent perturbations of this balance due to a brain pathology, drug administration, or therapy can lead to unfavorable long-term outcomes such as premature depletion of the RGLs, decreased AHN, and cognitive deficit. Memantine, a drug used for alleviating the symptoms of Alzheimer’s disease, and electroconvulsive seizure (ECS), a procedure used for treating drug-resistant major depression or bipolar disorder, are known strong AHN inducers; they were earlier demonstrated to increase numbers of dividing RGLs. Here, we demonstrated that 1-month stimulation of quiescent RGLs by either memantine or ECS leads to premature exhaustion of their pool and altered AHN at later stages of life and that aging of the brain modulates the ability of the quiescent RGLs to be recruited into the cell cycle by these AHN inducers. Our findings support the aging-related divergence of functional features of quiescent RGLs and have a number of implications for the practical assessment of drugs and treatments with respect to their action on quiescent RGLs at different stages of life in animal preclinical studies.
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Data Availability
All quantitative data are contained within the article. Original microscopy image data sets reported in this paper will be shared by the corresponding author, Dr. Oleg Podgorny (olegpodgorny@inbox.ru), upon request.
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This study was funded by the Russian Foundation for Basic Research, grant no. 19–29-04016 (to O.V.P.); the Ministry of Science and Higher Education of the Russian Federation, grant no. 075–15-2019–1789 to the Center for Precision Genome Editing and Genetic Technologies for Biomedicine (to O.V.P.); and the state assignment of the Ministry of Science and Higher Education of the Russian Federation for 2021–2023 (V.A.A. and N.V.G.).
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V.V.B., N.V.G., and O.V.P. designed the experiments. D.I.M., V.A.A., M.A.G., and A.D.P. performed and analyzed the experiments. N.V.G., and O.V.P. interpreted the results and wrote the manuscript. V.V.B. edited the manuscript. All authors read and approved the final manuscript.
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Supplementary file1. Online Resource 1 A cell of the EdU+BrdU-GFP+GFAP+process+ phenotype (a de novo dividing bona fide RGL stem cell). The video illustrates a Z-series of consecutive optical slices obtained using the confocal microscope. The arrow shows the body of an EdU+BrdU- RGL stem cell. The arrowheads show a GFP+GFAP+ apical process of the RGL stem cell (AVI 4530 KB)
Supplementary file2. Online Resource 2 A cell of the EdU+BrdU-GFP+GFAP+process- phenotype (a de novo dividing presumptive RGL stem cell). The video illustrates a Z-series of consecutive optical slices obtained using the confocal microscope. The arrow shows the body of an EdU+BrdU- presumptive RGL stem cell (AVI 1095 KB)
Supplementary file3. Online Resource 3 A cell of the EdU+BrdU-GFP+GFAP-process- phenotype. The video illustrates a Z-series of consecutive optical slices obtained using the confocal microscope. The arrow shows the body of an EdU+BrdU-GFP+GFAP-process- cell (AVI 731 KB)
Supplementary file4. Online Resource 4 Two cells of the EdU+BrdU-GFP-GFAP-process- phenotype. The video illustrates a Z-series of consecutive optical slices obtained using the confocal microscope. The arrows show bodies of two EdU+BrdU-GFP-GFAP-process- cell (AVI 3454 KB)
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Maltsev, D.I., Aniol, V.A., Golden, M.A. et al. Aging Modulates the Ability of Quiescent Radial Glia-Like Stem Cells in the Hippocampal Dentate Gyrus to be Recruited into Division by Pro-neurogenic Stimuli. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03746-5
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DOI: https://doi.org/10.1007/s12035-023-03746-5