Calcitonin gene-related peptide potentiated the excitatory transmission and network propagation in the anterior cingulate cortex of adult mice

Abstract

The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception-related prefrontal anterior cingulate cortex. However, less information is available for the functional roles of CGRP in cortical regions such as the anterior cingulate cortex (ACC). Recent studies have consistently demonstrated that long-term potentiation is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP 8-37 blocked CGRP-induced chemical long-term potentiation and the recruitment of inactive channels. CGRP-induced long-term potentiation was also blocked by N-methyl-D-aspartate (NMDA) receptor antagonist AP-5. Consistently, the application of CGRP increased NMDA receptor-mediated excitatory postsynaptic currents. Finally, we found that CGRP-induced long-term potentiation required the activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and protein kinase A. Genetic deletion of AC1 using AC1 −/− mice, an AC1 inhibitor NB001 or a protein kinase A inhibitor KT5720, all reduced or blocked CGRP-induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.

Cortical potentiation induced by calcitonin gene-related peptide (CGRP) in the insular cortex of adult mice

“…Previous studies of central synaptic transmission influenced by CGRP are mainly focused on the PBN, amygdala, the bed nucleus of the stria terminalis and spinal cords [17,34,35]. In the present study, we demonstrate that CGRP enhanced the synaptic transmission in the IC, which is like our recent study in the ACC [21]. We found that CGRP induced potentiation is NMDAR independent for the role of CGRP in the IC.…”

Cortical potentiation induced by calcitonin gene-related peptide (CGRP) in the insular cortex of adult mice

“…Our recent study showed that CGRP increased the excitatory synaptic transmission in the ACC [21]. Here we wanted to see if similar effect would be found in the IC, which also plays important roles in pain perception and chronic pain.…”

“…Cumulative evidences suggest that CGRP-containing pathways could convey nociceptive and visceral sensation from the posterior thalamus and parabrachial nuclear (PBN) complex to the IC and the amygdala [2]. Immunohistochemistry and in situ hybridization researches have also shown that CGRP and its receptors are expressed in some cortical areas, including the IC and anterior cingulate cortex (ACC) [21,22]. Our previous study indicates that CGRP may contribute to synaptic potentiation in the ACC [21].…”

“…Immunohistochemistry and in situ hybridization researches have also shown that CGRP and its receptors are expressed in some cortical areas, including the IC and anterior cingulate cortex (ACC) [21,22]. Our previous study indicates that CGRP may contribute to synaptic potentiation in the ACC [21]. The ACC and IC are two major cortical areas for pain perception [23][24][25][26], less information is available about the effects of CGRP on excitatory transmission within the IC.…”

Cystatin C promotes cognitive dysfunction in rats with cerebral microbleeds by inhibiting the ERK/synapsin Ia/Ib pathway

“…MED64 planar microelectrode array recording system was purchased from Alpha Med Science, Japan and used for electrophysiological recordings (32). ACSF for recording use was prepared containing 120 mM NaCl, 27 mM NaHCO 3 , 20 mM glucose, 1 mM NaH 2 PO 4 , 3 mM KCl, 2.6 mM CaCl 2 and 1 mM MgCl 2 .…”