Complete brain-type creatine kinase deficiency in mice blocks seizure activity and affects intracellular calcium kinetics.
OBJECTIVE
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 Ca(2+) 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 Ca(2+) removal speed following repetitive KCl-induced depolarizations.


CONCLUSIONS
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 Ca(2+) removal rate of elevated intracellular levels, we conclude that altered Ca(2+) clearance in CK--/-- neurons could play a role in the abnormal EEG and seizure activity.
Streijger
Femke
F
Department of Cell Biology, NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, Nijmegen, The Netherlands.
Scheenen
Wim J J M
WJ
van Luijtelaar
Gilles
G
Oerlemans
Frank
F
Wieringa
Bé
B
Van der Zee
Catharina E E M
CE
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003402:Creatine Kinase / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism; D052276:Creatine Kinase, BB Form / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism*; D052281:Creatine Kinase, Mitochondrial Form / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D004734:Energy Metabolism; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010433:Pentylenetetrazole; D011189:Potassium Chloride / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism*
D011189:Potassium Chloride; D003402:Creatine Kinase; D052276:Creatine Kinase, BB Form; D052281:Creatine Kinase, Mitochondrial Form; D002118:Calcium; D010433:Pentylenetetrazole