Abstract
Persistent dreadful memories and hyperarousal constitute prominent psychopathological features of posttraumatic stress disorder (PTSD). Here, we used a contextual fear conditioning paradigm to demonstrate that conditional genetic deletion of corticotropin-releasing hormone (CRH) receptor 1 within the limbic forebrain in mice significantly reduced remote, but not recent, associative and non-associative fear memories. Per os treatment with the selective CRHR1 antagonist DMP696 (3 mg/kg) attenuated consolidation of remote fear memories, without affecting their expression and retention. This could be achieved, if DMP696 was administered for 1 week starting as late as 24 h after foot shock. Furthermore, by combining electrophysiological recordings and western blot analyses, we demonstrate a delayed-onset and long-lasting increase in AMPA receptor (AMPAR) GluR1-mediated signaling in the dentate gyrus (DG) of the dorsal hippocampus 1 month after foot shock. These changes were absent from CRHR1-deficient mice and after DMP696 treatment. Inactivation of hippocampal GluR1-containing AMPARs by antisense oligonucleotides or philantotoxin 433 confirmed the behavioral relevance of AMPA-type glutamatergic neurotransmission in maintaining the high levels of remote fear in shocked mice with intact CRHR1 signaling. We conclude that limbic CRHR1 receptors enhance the consolidation of remote fear memories in the first week after foot shock by increasing the expression of Ca2+-permeable GluR1-containing AMPARs in the DG. These findings suggest both receptors as rational targets for the prevention and therapy, respectively, of psychopathology associated with exaggerated fear memories, such as PTSD.
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Acknowledgements
We thank A Siegmund for helpful comments on concept and implementation of the study and C Riebe for her comments on the manuscript. We also thank A Mederer, U Habersetzer, A Jurik, A Baumgartner, S Meyr, R Menz, and S Unkmeir for expert technical assistance. This work was partially supported by AGNP (CKT), the Bundesministerium für Bildung und Forschung within the framework of the NGFN-Plus (FKZ: 01GS08151 and 01GS08155; JMD and WW) and by the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215; JMD and WW).
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Thoeringer, C., Henes, K., Eder, M. et al. Consolidation of Remote Fear Memories Involves Corticotropin-Releasing Hormone (CRH) Receptor Type 1-Mediated Enhancement of AMPA Receptor GluR1 Signaling in the Dentate Gyrus. Neuropsychopharmacol 37, 787–796 (2012). https://doi.org/10.1038/npp.2011.256
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DOI: https://doi.org/10.1038/npp.2011.256
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