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The Journal of Neuroscience, November 15, 2002, 22(22):9868-9876

Localization of Phosphorylated cAMP Response Element-Binding Protein in Immature Neurons of Adult Hippocampus

Shin Nakagawa¹, Ji-Eun Kim¹, Rena Lee¹, Jingshan Chen¹, Takashi Fujioka¹, Jessica Malberg¹, Shuichi Tsuji², and R. S. Duman¹

¹ Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508, and ² Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan

Neurogenesis continues to occur in the adult hippocampus, although many of the newborn cells degenerate 1-2 weeks after birth. The number and survival of newborn cells are regulated by a variety of environmental stimuli, but very little is known about the intracellular signal transduction pathways that control adult neurogenesis. In the present study, we examine the expression of the phosphorylated cAMP response element-binding protein (pCREB) in immature neurons in adult hippocampus and the role of the cAMP cascade in the survival of new neurons. The results demonstrate that virtually all immature neurons, identified by triple immunohistochemistry for bromodeoxyuridine (BrdU) and polysialic acid-neural cell adhesion molecule (PSA-NCAM), are also positive for pCREB. In addition, upregulation of cAMP (via pharmacological inhibition of cAMP breakdown or by antidepressant treatment) increases the survival of BrdU-positive cells. A possible role for pCREB in the regulation of PSA-NCAM, a marker of immature neurons involved in neuronal remodeling and neurite outgrowth, is supported by cell culture studies demonstrating that the cAMP-CREB pathway regulates the expression of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM. These findings indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation and function, of newborn neurons.

Key words: dentate gyrus; neurogenesis; rolipram; PSA-NCAM; TUC-4; polysialyltransferases; antidepressant

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22229868-09$05.00/0

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