Complete brain-type creatine kinase deficiency in mice blocks seizure activity and affects intracellular calcium kinetics |
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Authors: | Femke Streijger,&dagger Wim J.J.M. Scheenen,&Dagger Gilles van Luijtelaar,Frank Oerlemans,Bé Wieringa, Catharina E.E.M. Van der Zee |
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Affiliation: | Department of Cell Biology, NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, Nijmegen, The Netherlands;;Department of Cellular Animal Physiology, EURON European Graduate School of Neuroscience, Donders Institute of Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands;;and Donders Centre for Cognition, Donders Institute of Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands |
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Abstract: | Purpose: Brain-type creatine kinase (CK-B) and ubiquitous mitochondrial creatine kinase (UbCKmit) act as components of local phosphocreatine ATP shuttles that help in the compartmentalization and maintenance of pools of high-energy phosphate molecules in both neurons and glial cells. We investigated the role of these brain-type creatine kinases during extreme energy-demanding conditions in vivo (generalized tonic–clonic seizures) and in vitro. Methods: The physiologic response of wild-types and mice lacking both CK-B and UbCKmit (CK--/--mice) to pentylenetetrazole (PTZ)–induced seizures was measured using electroencephalography (EEG) recordings and behavioral monitoring. In vitro intracellular Ca2+ kinetics in hippocampal granule neurons were monitored upon single and repetitive depolarizations. Results: PTZ induced in only a few CK--/-- mice PTZ seizure-like behavior, but in all wild-types a full-blown seizure. EEG analysis showed that preseizure jerking was associated with high-amplitude discharges. Wild-type EEG recordings showed continuous runs of rhythmic 4–6 Hz activity, whereas no rhythmic EEG activities were observed in the few CK--/-- mice that developed a behavioral seizure. All other CK--/-- mice displayed a sudden postictal depression without any development of a generalized seizure. Hippocampal granule neurons of CK--/-- mice displayed a higher Ca2+ removal speed following repetitive KCl-induced depolarizations. Discussion: Deficiency for creatine kinase is affecting brain energy metabolism and will likely contribute to the disturbance of seizure development. Because CK--/-- hippocampal neurons exhibited an increase in Ca2+ removal rate of elevated intracellular levels, we conclude that altered Ca2+ clearance in CK--/-- neurons could play a role in the abnormal EEG and seizure activity. |
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Keywords: | Pentylenetetrazole Behavioral seizure EEG 4–6 Hz Ca2+ clearance KCl-induced depolarization Ca2+ kinetics Hippocampus Granule neurons |
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