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Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

Molecular Psychiatry volume 12, pages 1042–1056 (2007)Cite this article

Abstract

Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to age-related processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT1B receptor (5-HT1BR), a candidate gene for 5-HT-mediated age-related functions. We show that the lack of 5-HT1BR (Htr1bKO mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1bKO mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1bKO mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1bKO mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.

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Acknowledgements

We thank Irwin Lucki and Anita Bechtholt for help with additional rodent support, Ruomei Liang for technical help, and David Lewis and Karoly Mirnics for helpful comments on the manuscript. This work was supported by NIMH (ES).

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    E Sibille, J Su & J Joeyen-Waldorf

  2. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    E Sibille & C Glorioso

  3. EA3248 Psychobiologie des émotions, Faculté des Sciences et Techniques, Université François Rabelais, Tours, France

    S Leman, A M Le Guisquet, Y Ibarguen-Vargas & C Belzung

  4. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

    G C Tseng

  5. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    M Pezzone

  6. Center for Neurobiology and Behavior, Columbia University, New York, NY, USA

    R Hen

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  1. E Sibille
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Correspondence to E Sibille or C Belzung.

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Sibille, E., Su, J., Leman, S. et al. Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity. Mol Psychiatry 12, 1042–1056 (2007). https://doi.org/10.1038/sj.mp.4001990

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