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Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility

Authors

  • Carolina R. Jost,

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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    • *

      Present address: Department of Molecular Cell Biology, Sylvius Laboratory, University of Leiden, PO Box 9503, 2300 RA Leiden, The Netherlands.

  • Catharina E. E. M. Van der Zee,

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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  • Henricus J. A. In ‘t Zandt,

    1. Department of Radiology, University Medical Center St. Radboud, University of Nijmegen, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands
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  • Frank Oerlemans,

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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  • Michel Verheij,

    1. Department of Psychoneuro-pharmacology, University Medical Center St. Radboud, 8 University of Nijmegen, Geert Grooteplein 21, 6525 GA, Nijmegen, The Netherlands
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  • Femke Streijger,

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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  • Jack Fransen,

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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  • Arend Heerschap,

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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  • Alexander R. Cools,

    1. Department of Psychoneuro-pharmacology, University Medical Center St. Radboud, 8 University of Nijmegen, Geert Grooteplein 21, 6525 GA, Nijmegen, The Netherlands
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  • Bé Wieringa

    1. Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands
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: Dr Bé Wieringa, as above.
E-mail: b.wieringa@ncmls.kun.nl

Abstract

Creatine kinases are important in maintaining cellular-energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine-like compounds. Herein we examine whether ablation of the cytosolic brain-type creatine kinase (B-CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B-CK (B-CK–/–) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra- and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr ⇆ ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B-CK–/– animals showed diminished open-field habituation. In the water maze, adult B-CK–/– mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24-month-old, aged B-CK–/– mice, on top of the age-related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole-induced seizures (creating a high-energy demand) was observed in B-CK–/– mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho-creatine shuttle provides compensation for the loss of B-CK in the brain. Our studies indicate a role for the creatine–phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B-CK can be compensated for by other systems in the versatile and robust metabolic-energy network of the brain.

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