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GABAergic compensation in connexin36 knock-out mice evident during low-magnesium seizure-like event activity

Abstract
Gap junctions within the cerebral cortex may facilitate cortical seizure formation by their ability to synchronize electrical activity. To investigate this, one option is to compare wild-type (WT) animals with those lacking the gene for connexin36 (Cx36 KO); the protein that forms neuronal gap junctions between cortical inhibitory cells. However, genetically modified knock-out animals may exhibit compensatory effects; with the risk that observed differences between WT and Cx36 KO animals could be erroneously attributed to Cx36 gap junction effects. In this study we investigated the effect of GABAA-receptor modulation (augmentation with 16 μM etomidate and blockade with 100 μM picrotoxin) on low-magnesium seizure-like events (SLEs) in mouse cortical slices. In WT slices, picrotoxin enhanced both the amplitude (49% increase, p = 0.0006) and frequency (37% increase, p = 0.005) of SLEs; etomidate also enhanced SLE amplitude (18% increase, p = 0.003) but reduced event frequency (25% decrease, p < 0.0001). In Cx36 KO slices, the frequency effects of etomidate and picrotoxin were preserved, but the amplitude responses were abolished. Pre-treatment with the gap junction blocker mefloquin in WT slices did not significantly alter the drug responses, indicating that the reduction in amplitude seen in the Cx36 KO mice was not primarily mediated by their lack of interneuronal gap junctions, but was rather due to pre-existing compensatory changes in these animals. Conclusions from studies comparing seizure characteristics between WT and Cx36 KO mice must be viewed with a degree of caution because of the possible confounding effect of compensatory neurophysiological changes in the genetically modified animals.
Type
Journal Article
Type of thesis
Series
Citation
Voss, L.J., Melin, S., Jacobson, G. & Sleigh, J.W. (2010). GABAergic compensation in connexin36 knock-out mice evident during low-magnesium seizure-like event activity. Brain Research, available online 8 September 2010.
Date
2010
Publisher
Elsevier
Degree
Supervisors
Rights
This is an author’s accepted version of an article published in the journal: Brain Research. © 2010 Brain Research.