Abstract
There is considerable interest in examining the genes that may contribute to anxiety. We examined the function of ERK/MAPK in the acquisition of conditioned fear, as measured by fear-potentiated startle (FPS) in mice as a model for anticipatory anxiety in humans. We characterized the following for the first time in the mouse: (1) the expression of the ERK/MAPK signaling pathway components at the protein level in the lateral amygdala (LA); (2) the time course of activation of phospho-activated MAPK in the LA after fear conditioning; (3) if pharmacological inhibition of pMAPK could modulate the acquisition of FPS; (4) the cell-type specificity of pMAPK in the LA after fear conditioning. Using western blot and immunohistochemistry techniques and injecting the MEK inhibitor U0126 in the LA, we showed the following: (1) both MEK1/MEK2 and ERK1/ERK2 were co-expressed in the LA of the adult mouse brain; (2) there is a peak of pMAPK at 60 min after fear conditioning; (3) the ERK/MAPK signaling pathway activation is essential for the acquisition of an FPS response; (4) at 60 min, the pMAPK are exclusively neuronal and not glial. These results emphasize the importance of this signaling pathway in the acquisition of conditioned fear in the mouse. Given the widely held view that conditioned fear models the essential aspects of anxiety disorders, the results confirm the ERK/MAPK signaling pathway as a molecular target for the treatment of anxiety disorders in the clinic.
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Acknowledgements
BDB is particularly indebted with Dr Vera Pedersen for her generous support with surgery and histological analysis in the first phases of the pharmacological studies; and with Johanna Neumann for helping with the IHC during the analysis of the time course of activated pMAPK. This work has been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), Förderkennzeichen 01GR430, and by the European Union (FP6, EUMODIC, LSHG-CT-2006-037188). We are responsible for the contents of this publication.
BDB performed the experiments, participated in the design of the study and wrote the manuscript. MK gave her contribution in the statistical analysis and with the FPS experiments. DMVW participated in the supervision of the histological procedures. WAF gave his contribution in the establishment of the FPS procedures. SMH and WW participated in the design and coordination of the study. All authors read and approved the final manuscript.
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Di Benedetto, B., Kallnik, M., Weisenhorn, D. et al. Activation of ERK/MAPK in the Lateral Amygdala of the Mouse is Required for Acquisition of a Fear-Potentiated Startle response. Neuropsychopharmacol 34, 356–366 (2009). https://doi.org/10.1038/npp.2008.57
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DOI: https://doi.org/10.1038/npp.2008.57
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