The biological role of the brain specific creatine kinase energy system in mice. A behavioral approach.

Abstract

For any living cell it is essential to keep energy demand and production well balanced, and have energy homeostasis - i.e. ATP level - under tight regulation. Cells maintain their ATP level and viability by either respiration or glycolysis, whereby the energy provided is needed for the synthesis and modification of small and macromolecular constituents of the cell, for cellular movement, maintenance of osmolar and electrical gradients, molecular transport, maintenance of protein integrity, and in warm-blooded animals, for the generation of body heat. The cellular network for allocation of ATP and distribution of high-energy phosphate groups among phosphometabolites in mammalian cells consists of several redundant pathways, in which glycolytic enzymes, members of the creatine kinase and adenylate kinase families of enzymes and nucleoside diphosphate kinases play a determining role. Creatine kinase (CK) is expressed in various tissues. The function of the enzyme is the catalysis of the reversible conversion of phosphocreatine to creatine, consuming ADP and generating ATP. In tissues that consume ATP rapidly, like skeletal muscle, heart and brain, creatine phosphate serves as a reservoir for the rapid generation of ATP in periods during which energy consumption threatens to exceed energy production. Although this system has been extensively studied in-vitro and in-vivo, it is still largely unknown how its proposed functions translate into biological significance in the intact animal. In the study described in this thesis much effort was spent to investigate the role of the brain specific creatine kinase-phosphocreatine circuit. Using gene-knockout approaches we have generated mice strains that carry null mutations for either cytosolic BCK (BCK-/- mice) or mitochondrial UbCKmit (UbCKmit-/- mice), or for both enzymes in double knockouts (CK--/-- mice). For phenotyping of these mice, a battery of many different behavioral paradigms was developed and used to study the relationship between phosphocreatine-creatine energetics and task performance