Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus.
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.
Nakagawa
Shin
S
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Kim
Ji-Eun
JE
Lee
Rena
R
Chen
Jingshan
J
Fujioka
Takashi
T
Malberg
Jessica
J
Tsuji
Shuichi
S
Duman
R S
RS
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012794:Sialic Acids / Q000096:biosynthesis; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism
D000928:Antidepressive Agents; D000943:Antigens, Differentiation; D001973:Bromodeoxyuridine; D005576:Colforsin; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D005473:Fluoxetine; D039842:Neural Cell Adhesion Molecule L1; D020889:Rolipram; D017367:Selective Serotonin Reuptake Inhibitors; D012794:Sialic Acids; D012799:Sialyltransferases; C103469:polysialyl neural cell adhesion molecule; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase