FoxO6 regulates memory consolidation and synaptic function
- Dervis A.M. Salih1,2,
- Asim J. Rashid3,12,
- Damien Colas2,4,12,
- Luis de la Torre-Ubieta5,6,12,
- Ruo P. Zhu1,2,
- Alexander A. Morgan7,8,
- Evan E. Santo9,
- Duygu Ucar1,
- Keerthana Devarajan1,
- Christina J. Cole3,
- Daniel V. Madison2,10,
- Mehrdad Shamloo2,11,
- Atul J. Butte7,
- Azad Bonni5,6,
- Sheena A. Josselyn3 and
- Anne Brunet1,2,13
- 1Department of Genetics,
- 2Stanford Institute for Neuro-Innovation and Translational Neuroscience, Stanford University, Stanford, California 94305, USA;
- 3Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada;
- 4Department of Biology, Stanford University, Stanford, California 94305, USA;
- 5Department of Neurobiology,
- 6Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 7Department of Pediatrics,
- 8Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA;
- 9Department of Oncogenomics, Academic Medical Center (AMC), Amsterdam 1105 AZ, The Netherlands;
- 10Department of Molecular and Cellular Physiology,
- 11Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, California 94305, USA
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↵12 These authors contributed equally to this work.
Abstract
The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.
Keywords
- consolidation
- FoxO transcription factors
- hippocampus
- insulin signaling
- learning and memory
- synaptic function
Footnotes
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↵13 Corresponding author
E-mail anne.brunet{at}stanford.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.208926.112.
- Received April 15, 2012.
- Accepted November 5, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.