Complete brain‐type creatine kinase deficiency in mice blocks seizure activity and affects intracellular calcium kinetics

Summary 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.