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

Abstract

SUMMARYPurpose: 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 highenergy phosphate molecules in both neurons and glial cells. We investigated the role of these braintype creatine kinases during extreme energydemanding conditions in vivo (generalized tonicclonic 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 highamplitude 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. 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 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.

Zebrafish as a Model for Epilepsy-Induced Cognitive Dysfunction: A Pharmacological, Biochemical and Behavioral Approach

“…Abnormal alteration of neurotransmitters levels has been found to be closely associated with many neurological diseases including epilepsy ( Huguenard, 2003 ). One of the reasons for the epileptic seizure and cognition in clinical conditions is neurotransmitter modulations by both epilepsy and AEDs ( Park and Kwon, 2008 ; Kleen et al, 2010 ). LC–MS/MS method was used to quantify the neurotransmitters simultaneously in zebrafish brain ( Santos-Fandila et al, 2015 ).…”

The creatine kinase system and pleiotropic effects of creatine

“…In line with earlier findings that CK is crucially involved in local ATP regeneration in the vicinity of the SR Ca 2+ -ATPase pump (Rossi et al 1990), it was shown with CK knockout mice that the CK system is indeed essential for optimal refill of the SR Ca 2+ store in skeletal muscle (de Groof et al 2002). According to more recent data, CK, however, is not only important for Ca 2+ cycling in muscle, but also in the brain, as shown with brain CK knockouts, where brain Ca 2+ kinetics were affected (Streijger et al 2010). Interestingly, Cr supplementation of myogenic cells from mdx dystrophic mice improves intracellular Ca 2+ handling (Pulido et al 1998) and Cr supplementation of athletes results in shortening of muscle relaxation times in vivo, presumably by improving SR-Ca 2+ -pump function and intracellular Ca 2+ handling (van Leemputte et al 1999).…”

Cognition and dementia in older patients with epilepsy

“…Moreover, it is now also appreciated that a major contribution to cognitive impairment in people with epilepsy is seizure activity, regardless of the underlying pathological cause of seizures ( Holmes, 2015 ). In fact, although it has long been acknowledged that status epilepticus or recurrent seizures can impact upon cognition, findings in both animal models and humans demonstrate that interictal spikes or IEDs can also disrupt cognitive function ( Kleen et al , 2010 , 2013 ) even if remote to the ictal onset zone ( Ung et al , 2017 ).…”