Abstract
The relationships among neuropeptide, calcitonin gene-related peptide (CGRP), and memory formation remain unclear. Here, we showed that the intracerebroventricular administration of CGRP impaired the traumatic fear memories, in a widely studied animal model of post-traumatic stress disorder. We found that CGRP administration suppressed fear memory by increasing neuronal PAS domain protein 4 (Npas4), phosphorylated histone deacetylase 5 (HDAC5), and protein kinase D (PKD). We also discovered that Npas4 knockdown inhibited CGRP-mediated fear memory. CGRP decreased the binding between HDAC5 and the Npas4 enhancer site and increased the binding between acetylated histone H3 and the Npas4 enhancer site. The pharmacological inhibition or knockdown of PKD attenuated the CGRP-mediated impairment of fear memory and the increased phosphorylation of HDAC5 and Npas4 expression. Our findings demonstrated that the CGRP-PKD pathway was associated with the histone H3 acetylation-Npas4 pathway. These results suggested a novel function for CGRP on fear memory, through epigenetic regulation.
Highlights
The relationships among neuropeptide, calcitonin gene-related peptide (CGRP), and memory formation remain unclear
We identified a novel signaling mechanism, through which CGRP signaling increases the levels of protein kinase D (PKD), phosphorylated histone deacetylase 5 (HDAC5), acetylated Histone H3, and Npas[4] in the mouse hippocampus, and demonstrated that this regulatory process is essential for the suppression of fear memory retention
The present study showed that CGRP suppresses fear memory retention by increasing phosphorylated HDAC5, acetylated histone H3, and Npas[4] levels in the mouse hippocampus (Fig. 5)
Summary
The relationships among neuropeptide, calcitonin gene-related peptide (CGRP), and memory formation remain unclear. The pharmacological inhibition or knockdown of PKD attenuated the CGRP-mediated impairment of fear memory and the increased phosphorylation of HDAC5 and Npas[4] expression. Our findings demonstrated that the CGRP-PKD pathway was associated with the histone H3 acetylation-Npas[4] pathway These results suggested a novel function for CGRP on fear memory, through epigenetic regulation. CGRP was found to attenuate the learning impairments induced by dizocilpine, an N-methyl-D-aspartate (NMDA) receptor antagonist, as assessed using a step-down, passive avoidance task[8]. In contrast with these findings, more recently, Wu et al.[9] reported that CGRP induced the extinction of fear memories in the central nucleus of the amygdala in rats. Npas4-deficient mice showed critical deficits in cognitive deficit hyperactivity and behavioral impairments[12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
