Calcitonin gene‐related peptide erases the fear memory and facilitates long‐term potentiation in the central nucleus of the amygdala in rats

Abstract

Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase (AC) and protein kinase A (PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. Here, we reported the importance of CGRP and CGRP1 receptor for synaptic plasticity in the CeA and the extinction of fear memory in rats. Our electrophysiological and behavioral in vitro and in vivo results showed exogenous application of CGRP induced an immediate and lasting longterm potentiation in the basolateral nucleus of amygdala-CeA pathway, but not in the lateral nucleus of amygdala-CeA pathway, while bilateral intra-CeA infusion CGRP (0, 5, 13 and 21 lM/side) dose dependently enhanced fear memory extinction. The effects were blocked by CGRP1 receptor antagonist ), N-methyl-D-aspartate receptors antagonist MK801 and PKA inhibitor H89. These results demonstrate that CGRP can lead to long-term potentiation of basolateral nucleus of amygdala-CeA pathway through a PKA-dependent postsynaptic mechanism that involved N-methyl-D-aspartate receptors and enhance the extinction of fear memory in rats. Together, the results strongly support a pivotal role of CGRP in the synaptic plasticity of CeA and extinction of fear memory. Keywords: calcitonin gene-related peptide, central nucleus of amygdala, fear extinction, long-term potentiation, synaptic plasticity. The neuropeptides play diverse and critical roles in regulating neuronal structures and functions in the central nervous system (Brain and Cox 2006;Sharf et al. 2008;Lyons and Thiele 2010). However, the role of neuropeptides in synaptic plasticity is less well known than that of classical neuronal transmitters, such as glutamate and c-aminobutyric acid (GABA). Calcitonin gene-related peptide (CGRP) is produced by calcitonin gene and expressed throughout the central and peripheral nervous system, especially in the nucleus accumbens, the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), Received February 10, 2015; revised manuscript received May 10, 2015; accepted July 1, 2015. Address correspondence and reprint requests to Dr Fang Wang, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, HUST, Number 13, Hangkong Road, Wuhan, Hubei 430030, China. E-mail: wangfangtj0322@163.com Abbreviations used: ACSF, artificial cerebrospinal fluid; AMPA, alphaamino-3-hydroxy-5-methylisoxazole-4-propionate; BLA, basolateral nucleus of amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CGRP, calcitonin gene-related peptide; CS, conditioned stimulus; fEPSP, field excitatory postsynaptic potential; LA, lateral nucleus of amygdala; LTP, long-term potentiation; NAc, nucleus accumbens; PFC, prefrontal cortex; US, unconditioned stimulus.

Potentiation of NMDA receptor-mediated synaptic transmission at the parabrachial-central amygdala synapses by CGRP in mice

“…22 (recording at 31℃), by Wu et al. 23 (at room temperature), and in this study (at room temperature) would suggest that the lower temperature used in this study and that by Wu et al. 23 would not resulted in the absence of this CGRP effect.…”

Ryanodine‐ and CaMKII‐dependent release of endogenous CGRP induces an increase in acetylcholine quantal size in neuromuscular junctions of mice

“…We hypothesized that the release of stored calcium by ryanodine may selectively stimulate the exocytosis of CGRP‐containing LDCVs, which will be followed by the increase in MEPP amplitude as the result of activation of CGRP receptors by released endogenous CGRP. To test this hypothesis, we studied the action of 0.1 μM of ryanodine in the presence of truncated CGRP (CGRP 8‐37 , 1 μM) which is widely used as CGRP‐receptor blocker (Gaydukov et al., 2016; Han, Adwanikar, Li, Ji, & Neugebauer, 2010; Hay, Garelja, Poyner, & Walker, 2017; Wu et al., 2015). We have shown that CGRP 8‐37 alone had no significant effect on MEPP amplitude (Gaydukov et al., 2016).…”

Npas4 impairs fear memory via phosphorylated HDAC5 induced by CGRP administration in mice

“…CGRP was also reported to attenuate learning impairments induced by the NMDA receptor antagonist dizocilpine (8). More recently, however, Wu et al reported the CGRP-induced extinction of fear memory in the central nucleus of the amygdala in rats (9). Thus, several studies have reported that CGRP might affect memory formation, but the results have been controversial.…”

“…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 reported that CGRP induced the extinction of fear memories in the central nucleus of the amygdala in rats (9). Thus, CGRP may modulate fear memory processing; however, whether CGRP enhances fear memory retention and what signaling mechanisms it acts through remain unclear.…”