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The Journal of Neuroscience, February 6, 2008, 28(6):1374-1384; doi:10.1523/JNEUROSCI.3632-07.2008

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Neurobiology of Disease
Chronic Fluoxetine Stimulates Maturation and Synaptic Plasticity of Adult-Born Hippocampal Granule Cells

Jing-Wen Wang,^1,4 Denis J. David,² James E. Monckton,⁴ Fortunato Battaglia,³ and René Hen⁴

¹Department of Biological Sciences, Columbia University, New York, New York 10027, ²EA 3544 Faculte de Pharmacy, Universite Paris-Sud, Chatenay-Malabry 92296, France, ³Department of Physiology and Pharmacology, City College of New York, New York, New York 10031, and ⁴Departments of Neuroscience and Psychiatry, Columbia University, New York, New York 10032

Correspondence should be addressed to Dr. René Hen, Departments of Neuroscience and Psychiatry, Columbia University, Kolb Research Annex Room 767, 1051 Riverside Drive, New York, NY 10032. Email: rh95{at}columbia.edu

Chronic treatments with selective serotonin reuptake inhibitors (SSRIs) have been shown to increase hippocampal neurogenesis. However, it is not known whether SSRIs impact the maturation and functional integration of newborn neurons. Here we examined the effects of subchronic and chronic fluoxetine on the structural and physiological properties of young granule cells. Our results show that doublecortin-positive immature neurons displayed increased dendritic arborization after chronic fluoxetine treatment. In addition, chronic but not subchronic fluoxetine elicited a decrease in the number of newborn neurons expressing immature markers and a corresponding increase in those expressing mature markers. These results suggest that chronic fluoxetine accelerates the maturation of immature neurons. We also investigated the effects of fluoxetine on a form of neurogenesis-dependent long-term potentiation (LTP) in the dentate gyrus. This form of LTP was enhanced by chronic fluoxetine, and ablation of neurogenesis with x-irradiation completely blocked the effects of chronic fluoxetine on LTP. Finally, we demonstrated that the behavioral effect of fluoxetine in the novelty-suppressed feeding test requires chronic administration and is blocked by x-irradiation. These results show that the effects of fluoxetine on LTP and behavior both require neurogenesis and follow a similar delayed time course. The effects of chronic fluoxetine on the maturation and functional properties of young neurons may therefore be necessary for its anxiolytic/antidepressant activity and contribute to its delayed onset of therapeutic efficacy.

Key words: dentate gyrus; adult neurogenesis; dendrites; long-term potentiation; LTP; depression; selective serotonin reuptake inhibitors; SSRIs; hippocampus; antidepressants

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Received Aug. 9, 2007; revised Nov. 10, 2007; accepted Dec. 15, 2007.

Correspondence should be addressed to Dr. René Hen, Departments of Neuroscience and Psychiatry, Columbia University, Kolb Research Annex Room 767, 1051 Riverside Drive, New York, NY 10032. Email: rh95{at}columbia.edu

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