Consolidation of remote fear memories involves corticotropin releasing hormone (CRH) receptor type 1-mediated enhancement of AMPA receptor GluR1 signaling in the dentate gyrus
Résumé
Persistent dreadful memories and hyperarousal constitute prominent psychopathological features of posttraumatic stress disorder (PTSD). Here we used a contextual fear conditioning paradigm to demonstrated 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 (3mg/kg) attenuated the consolidation of remote fear memories, without affecting their expression and retention. This could be achieved, if DMP696 was administered for one week starting as late as 24h after the foot shock. Furthermore, by combining electrophysiological recordings and Western blot analyses we demonstrate a delayed-onset and long-lasting increase in AMPA receptor GluR1-mediated signaling in the dentate gyrus 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 technology or local treatment with philantotoxin 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 the foot shock by increasing the expression of Ca2+-permeable GluR1-containing AMPA receptors in the dentate gyrus. These findings suggest both receptors as rational targets for the prevention and therapy, respectively, of psychopathology associated with exaggerates fear memories, such as PTSD.
Domaines
Pharmacologie
Origine : Fichiers produits par l'(les) auteur(s)
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