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Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

Molecular Psychiatry volume 12, pages 1118–1128 (2007)Cite this article

Abstract

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.

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Acknowledgements

We thank Dr J de Felipe (Cajal Institute) for his advice with synaptic markers, Dr MA Arevalo for his help with the pPCR and Dr J Torrado (Universidad Complutense, Madrid) for his generous help with IGF-I microspheres. We also appreciate the invaluable help of J Sancho, I Alvarez and M Garcia. This work was supported by Grants SAF2001-1722 and 2004-0446.

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  1. Jl Trejo and J Piriz: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Neuroendocrinology, Cajal Institute, CSIC, Madrid, Spain

    Jl Trejo, J Piriz, M V Llorens-Martin, A M Fernandez, M Bolós & I Torres-Aleman

  2. Department of Medicine, Mt Sinai Hospital, New York, NY, USA

    D LeRoith

  3. Department of Neuroanatomy, School of Medicine, Autonoma University, Madrid, Spain

    A Nuñez

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  1. Jl Trejo
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Trejo, J., Piriz, J., Llorens-Martin, M. et al. Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol Psychiatry 12, 1118–1128 (2007). https://doi.org/10.1038/sj.mp.4002076

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