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The Journal of Neuroscience, November 15, 2000, 20(22):8435-8442

Insulin-Like Growth Factor-I Promotes Neurogenesis and Synaptogenesis in the Hippocampal Dentate Gyrus during Postnatal Development

John R. O'Kusky¹, Ping Ye², and A. Joseph D'Ercole²

¹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9, and ² Department of Pediatrics, Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7220

The in vivo actions of insulin-like growth factor-I (IGF-I) on the growth and development of the hippocampal dentate gyrus were investigated in transgenic mice that overexpress IGF-I postnatally in the brain and in normal nontransgenic littermate controls. Stereological analyses of the dentate gyrus were performed by light and electron microscopy on days 7, 14, 21, 28, 35, and 130 to determine postnatal changes in the numerical density and total number of neurons and synapses. The volumes of both the granule cell layer and the molecular layer of the dentate gyrus were significantly increased by 27-69% in transgenic mice after day 7, with the greatest relative increases occurring by day 35. Although the numerical density of neurons in the granule cell layer did not differ significantly between transgenic and control mice at any age studied, the total number of neurons was significantly greater in transgenic mice by 29-61% beginning on day 14. The total number of synapses in the molecular layer was significantly increased by 42-105% in transgenic mice from day 14 to day 130. A transient increase in the synapse-to-neuron ratio was found in transgenic mice at postnatal days 28 and 35 but not at day 130. This finding indicates a disproportionate increase in synaptogenesis, exceeding that expected for the observed increase in neuron number. Our results demonstrate that IGF-I overexpression produces persistent increases in the total number of neurons and synapses in the dentate gyrus, indicating that IGF-I promotes both neurogenesis and synaptogenesis in the developing hippocampus in vivo.

Key words: insulin-like growth factor-I; IGF-I; hippocampus; dentate gyrus; neurogenesis; synaptogenesis; stereology

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20228435-08$05.00/0

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