Creatine Synthesis and Supplementation Regulates Central Nervous System Postnatal Development and Injury

Abstract

Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. Exactly how endogenously synthesized creatine regulates central nervous system (CNS) function remains poorly understood. In this study, magnetic resonance spectroscopy (MRS) of adult mouse brains revealed creatine synthesis is primarily dependent on the expression of the enzyme guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, I generated a mouse line by knocking-in a green fluorescent protein (GFP) which is expressed upon excision of Gamt. During early postnatal life, Gamt was expressed with neural stem cells, neuronal precursor cells, astrocytes and oligodendrocytes. Starting at two weeks old, I found that Gamt is uniquely expressed in mature oligodendrocytes during active myelination in the postnatal CNS, with expression continuing into adulthood. Homozygous deletion of Gamt resulted in the significant reduction of mature oligodendrocytes, and delayed myelination in the corpus callosum. Moreover, the absence of Gamt expression also resulted in altered AMPK signaling in the brain, and reduced brain creatine kinase expression in cortical neurons. The dependence of timely myelination on creatine synthesis, which was also observed after experimental demyelination in mice with conditional deletion of Gamt in oligodendrocytes, led to delayed remyelination. As half of daily creatine comes from diet, I also showed that creatine and cyclocreatine supplementation in a cuprizone-mediated demyelination can enhance remyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development and that altered energetic metabolism in the CNS and delayed myelination through the disruption of creatine synthesis in oligodendrocytes may contribute to CCDS.