• Wenbin Wang, Yung-Wei Pan, Junhui Zou, Tan Li, Glen M Abel, Richard D Palmiter, Daniel R Storm, and Zhengui Xia.
• Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195; Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington 98195; Department of Biochemistry and Genetics, Zhejiang University, Hangzhou, Zhejiang 310058, China; and Howard Hughes Medical Institute, Department of Biochemistry and Department of Pharmacology, University of Washington, Seattle, Washington 98195.
• J. Neurosci. 2014 Feb 5; 34 (6): 2130-47.

AbstractRecent studies have shown that inhibition of adult neurogenesis impairs the formation of hippocampus-dependent memory. However, it is not known whether increasing adult neurogenesis affects the persistence of hippocampus-dependent long-term memory. Furthermore, signaling mechanisms that regulate adult neurogenesis are not fully defined. We recently reported that the conditional and targeted knock-out of ERK5 MAP kinase in adult neurogenic regions of the mouse brain attenuates adult neurogenesis in the hippocampus and disrupts several forms of hippocampus-dependent memory. Here, we developed a gain-of-function knock-in mouse model to specifically activate endogenous ERK5 in the neurogenic regions of the adult brain. We report that the selective and targeted activation of ERK5 increases adult neurogenesis in the dentate gyrus by enhancing cell survival, neuronal differentiation, and dendritic complexity. Conditional ERK5 activation also improves the performance of challenging forms of spatial learning and memory and extends hippocampus-dependent long-term memory. We conclude that enhancing signal transduction of a single signaling pathway within adult neural stem/progenitor cells is sufficient to increase adult neurogenesis and improve the persistence of hippocampus-dependent memory. Furthermore, activation of ERK5 may provide a novel therapeutic target to improve long-term memory.

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