Consolidation of Remote Fear Memories Involves Corticotropin-Releasing Hormone (CRH) Receptor Type 1-Mediated Enhancement of AMPA Receptor GluR1 Signaling in the Dentate Gyrus

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 Ca(2+)-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.

Susceptibility to PTSD-Like Behavior Is Mediated by Corticotropin-Releasing Factor Receptor Type 2 Levels in the Bed Nucleus of the Stria Terminalis

“…Since indeed none of the protocols in our model showed significant long-term changes in CRFR1, we suggest that the initiation of the stress response has indeed subsided. In fact, Thoeringer et al (2012) show that traumatic memories in the hippocampus can be reversed by CRFR1 antagonists only within the first week after the trauma. So if CRFR1 activity does not regulate long-term responses to PTSD and PTSD is a pathology that can last for years, then the shutting off of the response to the trauma must be impaired.…”

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…Crh over-expression was followed by a decreased CRHR1 receptor density within the BNST suggesting that "behavioral effects may be mediated by enhanced CRH receptor signaling or compensatory changes in CRF receptor density within these structures" 66 . Importantly, CRH over-expression was impairing anxiety responses towards threat cues if administered prior to conditioning, and also, limbic CRHR1 was shown to be required for the enhancement of fear memory consolidation 8 . Together these data suggest an important role for CRHR1 in the formation and generalization of fear.…”

“…These data suggest an important role of CRHR1 in short-and long-term adaptive responses to stress, probably by attenuating the impact of circulating ACTH and CORT, while CRHR1 directly exerts negative effects on learning and hippocampal morphology as a response to stress. Further adding to this, it was shown that limbic CRHR1 enhances the consolidation of fear memories 8 .…”

“…8) was obtained from the national research initive "Panic-Net" founded by the Federal Ministry of Education and Research 36 ; details on the sample as well as the study workflow were previously published 32,37 . The diagnosis of PD/AG (co-morbid AG was an inclusion criterion, so all patients suffered thereof) was established by a structured clinical interview (CIDI) according to DSM-IV criteria 35 .…”

Stress effects on the hippocampus: a critical review

“…CORT has also been shown to interact with catecholamines in the basolateral amygdala to intensify long-term memory consolidation of emotional events . However, CRF1 receptor-deficient mice (deficient in CORT elevation) showed normal fear learning (Tovote et al 2005) and displayed decreased remote, but not recent, contextual fear memory (Thoeringer et al 2012).…”