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The Journal of Neuroscience, January 14, 2004, 24(2):319-328; doi:10.1523/JNEUROSCI.1065.03.2004

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Development/Plasticity/Repair
Activation of cAMP Signaling Facilitates the Morphological Maturation of Newborn Neurons in Adult Hippocampus

Takashi Fujioka, Aya Fujioka, and Ronald S. Duman

Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508

Previous studies have demonstrated that activation of the cAMP cascade, including the cAMP response element-binding protein (CREB), increases the proliferation and survival of newborn neurons in adult mouse hippocampus. In the present study, we determined whether the cAMP-CREB cascade also influences the morphological maturation of newborn neurons in the subgranular zone of the hippocampus. Rolipram, a selective inhibitor of the cAMP-specific phosphodiesterase type 4, was administered to activate the cAMP cascade, and neuronal morphology was determined by analysis of Golgi-impregnated neurons in the subgranular zone of hippocampus. Rolipram administration significantly increased the number of branch points and length of dendrites relative to vehicle treatment. Increased branch number and length were accompanied by increased levels of phosphorylated CREB, the active form of this transcription factor, in immature neurons. In contrast, the morphology of Golgi-impregnated neurons was not significantly influenced by rolipram treatment in inducible transgenic mice expressing a dominant-negative mutant of CREB in hippocampus. We also tested the influence of cAMP analogs in primary hippocampal cultures and found that activation of the cAMP pathway increased and inhibition of the cAMP cascade decreased the number of branches and length of processes as observed in vivo. These findings indicate that the cAMP-CREB cascade plays an important role in the differentiation and maturation of newborn neurons in hippocampus.

Key words: rolipram; phosphodiesterase type IV (PDE4); cAMP response element-binding protein (CREB); antidepressant; subgranular zone; dentate gyrus

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Received April 10, 2003; revised October 31, 2003; accepted November 5, 2003.

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