Conditional Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Is Not Associated with Anxiety/Depression-Like Behaviors

Junhui Zou,Zhengui Xia,Daniel R Storm,Wenbin Wang,Yung-Wei Pan,Glen M Abel

doi:10.1523/eneuro.0014-14.2015

Abstract

Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.

Highlights

Adult neurogenesis occurs in the subgranular zone of the dentate gyrus and the subventricular zone along the lat-Received September 3, 2014; accepted March 23, 2015; First published April 10, 2015. 1Author contributions: J.Z., D.R.S., and Z.X. designed research; J.Z., W.W., Y.-W.P., and G.M.A. performed research; J.Z., W.W., Y.-W.P., D.R.S., and Z.X. analyzed data; J.Z., D.R.S., and Z.X. wrote the paper; W.W., Y.-W.P., D.R.S., and Z.X. contributed unpublished reagents/analytic tools.We thank Dr Chay T
Inhibition of adult neurogenesis by targeted deletion of ERK5 is not associated with an increased level of anxiety in non-stressed mice Under normal conditions, ERK5 expression in the adult brain is limited to the neural stem/progenitor cells, transiently amplifying progenitors, and/or newborn neurons in the adult neurogenic regions including the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and the subventricular zone/rostral migratory stream
Adult Nestin-CreERTM/ ERK5loxP/loxP mice were treated with tamoxifen to induce erk5 gene deletion in the Nestin-expressing neural stem cells (ERK5 inducible knockout (icKO)), while vehicle-treated mice of the same genotype or ERK5loxP/loxP littermates treated with tamoxifen or vehicle were used as controls

Summary

Introduction

Adult neurogenesis occurs in the subgranular zone of the dentate gyrus and the subventricular zone along the lat-Received September 3, 2014; accepted March 23, 2015; First published April 10, 2015. 1Author contributions: J.Z., D.R.S., and Z.X. designed research; J.Z., W.W., Y.-W.P., and G.M.A. performed research; J.Z., W.W., Y.-W.P., D.R.S., and Z.X. analyzed data; J.Z., D.R.S., and Z.X. wrote the paper; W.W., Y.-W.P., D.R.S., and Z.X. contributed unpublished reagents/analytic tools.We thank Dr Chay T. Adult-born neurons in the dentate gyrus functionally integrate into the hippocampal circuitry and play a critical role in cognitive processes such as contextual and spatial memory and pattern separation. There is a link between adult neurogenesis and psychiatric disorders including anxiety and depression (Kheirbek et al, 2012; Petrik et al, 2012). Treatment of anxiety/depression with antidepressants normalizes the level of adult neurogenesis (Czéh et al, 2001; David et al, 2009; Koo et al, 2010; Garza et al, 2011). Studies that combined depression animal models and neurogenesis-ablation animal models suggest that intact adult neurogenesis is critical for antidepressant-mediated reversal of the depressive state (Santarelli et al, 2003; David et al, 2009; Revest et al, 2009; Koo et al, 2010; Surget et al, 2011)

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