Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination

Abstract: Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectroscopy of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a GFP, which is expressed on excision of Gamt. We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen-induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions, such as CCDS.

Parent Summary: This study used mouse models of GAMT deficiency to better understand creatine production in the central nervous system (which is defined as both the brain and spinal cord). Animal models are ultimately helpful for humans because researchers can perform experiments with animals that they would not be ethically allowed to do with people. These authors showed that the main source of the brain’s ability to make creatine is within types of brain cells called oligodendrocytes (pronounced “uh-leh-go-DEN-dro-sites”). These types of cells are responsible for building structures that wrap around nerve cells so that different parts of the brain can work together more efficiently; these structures, called myelin (pronounced “MY-eh-lin”), prevent brain activity from getting lost, like how coats wrapped around our bodies prevent our body heat from escaping. When GAMT was not expressed in these mouse brains, there was a delay in the brain’s ability to create myelin. However, dietary supplementation of creatine did help restart this process of creating myelin. In conclusion, these authors suggest that oligodendrocyte function may be an important mechanism in CCDS.

Link to article:  https://www.jneurosci.org/content/43/7/1143.abstract

PubMed: https://pubmed.ncbi.nlm.nih.gov/36732069/

Authors: Lauren M. Rosko, Tyler Gentile, Victoria N. Smith, Zeeba Manavi, George S. Melchor, Jingwen Hu, Nataliia V. Shults, Chris Albanese, Yichien Lee, Olga Rodriguez, & Jeffrey K. Huang

Key Terms: GAMT, animal study, in vitro, mutation study, supplements, basic science