Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus.
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.
Fujioka
Takashi
T
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Fujioka
Aya
A
Duman
Ronald S
RS
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000648:ultrastructure; D018891:Dentate Gyrus / Q000166:cytology; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D020889:Rolipram