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The Journal of Neuroscience, July 18, 2007, 27(29):7860-7868; doi:10.1523/JNEUROSCI.2051-07.2007

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Behavioral/Systems/Cognitive
cAMP Response Element-Binding Protein Deficiency Allows for Increased Neurogenesis and a Rapid Onset of Antidepressant Response

Tamar L. Gur,¹ Alana C. Conti,¹ Jessica Holden,¹ Anita J. Bechtholt,² Tiffany E. Hill,² Irwin Lucki,^1,2 Jessica E. Malberg,³ and Julie A. Blendy¹

Departments of ¹Pharmacology and ²Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ³Neuroscience Discovery, Wyeth Research, Princeton, New Jersey 08852

Correspondence should be addressed to Dr. Julie A. Blendy, Department of Pharmacology, Center for Neurobiology and Behavior, Translational Research Laboratories, 125 South 31st Street, Philadelphia, PA 19104-3403. Email: blendy{at}mail.med.upenn.edu

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREB mutant mice. Serotonin depletion decreased neurogenesis in CREB mutant mice to WT levels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREB mutant mice responded to chronic AD treatment in the NIH paradigm, only CREB mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment.

Key words: novelty-induced hypophagia; NIH; CREB; neurogenesis; DMI; mouse; depression

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Received Dec. 8, 2006; revised June 12, 2007; accepted June 18, 2007.

Correspondence should be addressed to Dr. Julie A. Blendy, Department of Pharmacology, Center for Neurobiology and Behavior, Translational Research Laboratories, 125 South 31st Street, Philadelphia, PA 19104-3403. Email: blendy{at}mail.med.upenn.edu

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