Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 Mitogen-Activated Protein Kinase Specifically in Adult Neurogenic Regions Impairs Contextual Fear Extinction and Remote Fear Memory

Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2012; 32(19):6444-55. DOI: 10.1523/JNEUROSCI.6076-11.2012
Source: PubMed


Although there is evidence suggesting that adult neurogenesis may contribute to hippocampus-dependent memory, signaling mechanisms responsible for adult hippocampal neurogenesis are not well characterized. Here we report that ERK5 mitogen-activated protein kinase is specifically expressed in the neurogenic regions of the adult mouse brain. The inducible and conditional knock-out (icKO) of erk5 specifically in neural progenitors of the adult mouse brain attenuated adult hippocampal neurogenesis. It also caused deficits in several forms of hippocampus-dependent memory, including contextual fear conditioning generated by a weak footshock. The ERK5 icKO mice were also deficient in contextual fear extinction and reversal of Morris water maze spatial learning and memory, suggesting that adult neurogenesis plays an important role in hippocampus-dependent learning flexibility. Furthermore, our data suggest a critical role for ERK5-mediated adult neurogenesis in pattern separation, a form of dentate gyrus-dependent spatial learning and memory. Moreover, ERK5 icKO mice have no memory 21 d after training in the passive avoidance test, suggesting a pivotal role for adult hippocampal neurogenesis in the expression of remote memory. Together, our results implicate ERK5 as a novel signaling molecule regulating adult neurogenesis and provide strong evidence that adult neurogenesis is critical for several forms of hippocampus-dependent memory formation, including fear extinction, and for the expression of remote memory.

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Available from: Chay Kuo, Mar 22, 2014
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    • "cognitive deficits (Filliat et al. 1999, 2007). However, increasing evidence suggests that neurogenesis may also be a contributory factor to nerve agent-induced long-term cognitive and behavioral disorders as impaired adult neurogenesis in rodents has been shown to be associated with defective spatial and contextual memory (Collombet et al. 2005; Gheusi et al. 2000; Joosen et al. 2009; Pan et al. 2012b; Saxe et al. 2006). Cognitive impairment and structural changes in the brain have been demonstrated in humans following nerve agent exposure and can result in long-term neurologic and behavior consequences such as depression and posttraumatic stress disorder (PTSD) (Abe et al. 2006; Hom et al. 1997; Miyaki et al. 2005; Ohbu et al. 1997; Rogers et al. 2009; Toomey et al. 2009; Yamasue et al. 2003) despite treatment with currently approved drugs to ameliorate signs and symptoms. "
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