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Neuron. 2016 Sep 21;91(6):1356-1373. doi: 10.1016/j.neuron.2016.08.009. Epub 2016 Sep 1.

Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits.

Author information

1
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
2
Departments of Neuroscience and Psychiatry, Columbia University, New York, NY 10032, USA.
3
Department of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
4
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
5
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
6
Neuroscience Center, Massachusetts General Hospital, Boston, MA 02129, USA.
7
Echelon Biosciences, Salt Lake City, UT 84108, USA.
8
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and University Hospital of Cologne, Joseph-Stelzmann-Straße 26, D-50931 Cologne, Germany.
9
Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University, 55128 Mainz, Germany.
10
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: asahay@mgh.harvard.edu.

Abstract

The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the DG. Rejuvenation of the DG by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.

PMID:
27593178
PMCID:
PMC5033725
DOI:
10.1016/j.neuron.2016.08.009
[Indexed for MEDLINE]
Free PMC Article

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