Large-scale mass spectrometry imaging investigation of consequences of cortical spreading depression in a transgenic mouse model of migraine.

Ricardo J Carreira,Arn M J M Van Den Maagdenberg,Walid M Abdelmoula,Benjamin Balluff,Else A Tolner,Sandra H Van Heiningen,Liam A Mcdonnell,Rene J Van Zeijl,Michel D Ferrari,Jouke Dijkstra,Reinald Shyti

doi:10.1007/s13361-015-1136-8

Ricardo J Carreira, Arn M J M Van Den Maagdenberg + Show 9 more

Open Access

https://doi.org/10.1007/s13361-015-1136-8

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Abstract

Cortical spreading depression (CSD) is the electrophysiological correlate of migraine aura. Transgenic mice carrying the R192Q missense mutation in the Cacna1a gene, which in patients causes familial hemiplegic migraine type 1 (FHM1), exhibit increased propensity to CSD. Herein, mass spectrometry imaging (MSI) was applied for the first time to an animal cohort of transgenic and wild type mice to study the biomolecular changes following CSD in the brain. Ninety-six coronal brain sections from 32 mice were analyzed by MALDI-MSI. All MSI datasets were registered to the Allen Brain Atlas reference atlas of the mouse brain so that the molecular signatures of distinct brain regions could be compared. A number of metabolites and peptides showed substantial changes in the brain associated with CSD. Among those, different mass spectral features showed significant (t-test, P < 0.05) changes in the cortex, 146 and 377 Da, and in the thalamus, 1820 and 1834 Da, of the CSD-affected hemisphere of FHM1 R192Q mice. Our findings reveal CSD- and genotype-specific molecular changes in the brain of FHM1 transgenic mice that may further our understanding about the role of CSD in migraine pathophysiology. The results also demonstrate the utility of aligning MSI datasets to a common reference atlas for large-scale MSI investigations.Graphical ᅟElectronic supplementary materialThe online version of this article (doi:10.1007/s13361-015-1136-8) contains supplementary material, which is available to authorized users.

Highlights

M atrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is a label-free techniqueRicardo J
We used MALDI-MSI combined with a newly developed pipeline that allows the automatic registration of MS datasets to mouse data contained in the Allen Brain Atlas [19], to investigate the biomolecular distribution in the brain after Cortical spreading depression (CSD) in a relevant mouse model of migraine
Our results revealed that CSD events affect the distribution of metabolites, peptides and proteins, in the cortex and in subcortical structures

Summary

Methods

Male 2- to 4-month-old transgenic FHM1 R192Q mice (carrying the human pathogenic missense mutation R192Q) and corresponding non-transgenic wild-type (WT) mice were used. Transgenic mice were generated by introducing the human pathogenic mutation in the mouse Cacna1a gene using a gene targeting approach, as described in [27]. All mice were kept in a normal 12:12 light/dark regime and food and water were available ad libitum. The 32 animals used in this study were divided into different groups according to the experimental conditions: WT-Naïve (five animals); WT-Sham (six animals); WT-CSD (five animals); R192Q-Naïve (five animals); R192Q-Sham (six animals); R192Q-CSD (five animals). All experiments were approved by the Animal Experiment Ethics Committee of Leiden University Medical Center.

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