NR2A contributes to genesis and propagation of cortical spreading depression in rats.

Fan Bu,Ruoxing Du,John P Quinn,Yi Li,Minyan Wang

doi:10.1038/srep23576

Abstract

Cortical spreading depression (CSD) is a transient propagating excitation of synaptic activity followed by depression, which is implicated in migraine. Increasing evidence points to an essential role of NR2A-containing NMDA receptors in CSD propagation in vitro; however, whether these receptors mediate CSD genesis in vivo requires clarification and the role of NR2A on CSD propagation is still under debate. Using in vivo CSD in rats with electrophysiology and in vitro CSD in chick retina with intrinsic optical imaging, we addressed the role of NR2A in CSD. We demonstrated that NVP-AAM077, a potent antagonist for NR2A-containing receptors, perfused through microdialysis probes, markedly reduced cortex susceptibility to CSD, but also reduced magnitude of CSD genesis in rats. Additionally, NVP-AAM077 at 0.3 nmol perfused into the contralateral ventricle, considerably suppressed the magnitude of CSD propagation wave and propagation rate in rats. This reduction in CSD propagation was also observed with TCN-201, a negative allosteric modulator selective for NR2A, at 3 μM, in the chick retina. Our data provides strong evidence that NR2A subunit contributes to CSD genesis and propagation, suggesting drugs selectively antagonizing NR2A-containing receptors might constitute a highly specific strategy treating CSD associated migraine with a likely better safety profile.

Highlights

Whether NR2A-containing receptors modulate susceptibility of the cortex to Cortical Spreading Depression (CSD) is unknown
MK-801 suppressed CSD genesis in a concentration dependent manner (Fig. 1, n = 6)
To confirm NR2A-containing NMDA receptors are involved in CSD propagation, we examined the effect of TCN-201 that was previously reported to have better selectivity for NR2A than NVP-AAM07717 in CSD propagation in chick retina

Summary

Introduction

Whether NR2A-containing receptors modulate susceptibility of the cortex to CSD is unknown. Whether NR2A-containing receptors contribute to CSD propagation is still a matter of debate[15,16]. We have demonstrated that inhibition of NR2A-containing receptors by NVP-AAM077, an antagonist that is preferably selective for NR2A at the concentration applied, resulted in suppression of CSD propagation in chick retina, a tissue which lacks blood vessels[15], suggesting involvement of neuronal and glial activity. Using blood oxygen level dependent (BOLD) fMRI approach, NR2A inhibition under TCN-201, a negative allosteric modulator selective for NR2A-containing NMDA receptors, application did not alter CSD propagation features in rats[16]. The primary aim of this study was to explore the role of NR2A-containing receptors in CSD genesis and propagation in rats by investigating effects of NVP-AAM077. The involvement of NR2A in CSD propagation was subsequently confirmed using another pharmacological tool TCN-201 at concentrations selective for binding to NR2A in chick retina

Objectives

Methods

Results

Conclusion