title: Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.
abstract: Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy.
authors: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Jing
authors: J
authors: Wang
authors: Denis
authors: D
authors: Gallagher
authors: Loren M
authors: LM
authors: DeVito
authors: Gonzalo I
authors: GI
authors: Cancino
authors: David
authors: D
authors: Tsui
authors: Ling
authors: L
authors: He
authors: Gordon M
authors: GM
authors: Keller
authors: Paul W
authors: PW
authors: Frankland
authors: David R
authors: DR
authors: Kaplan
authors: Freda D
authors: FD
authors: Miller
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002540:Cerebral Cortex / Q000196:embryology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008568:Memory / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007527:Isoenzymes; D008687:Metformin; D050882:CREB-Binding Protein; D011493:Protein Kinase C