Metformin attenuates developmental myelination

Developmental myelination is a protracted process spanning almost three decades. Many regions of the brain undergo developmental myelination throughout childhood and adolescence. Cognitive, motor, and behavioral performance rely on precise spatiotemporal development of myelin. Metformin, an FDA-approved treatment for Type II Diabetes Mellitus, can play a neuroprotective role in adult and aged rodent models of myelin loss by increasing oligodendrocyte production, modulating neuroinflammation, and accelerating myelin repair. However, metformin’s ability to influence developmental myelination remains largely unknown, in spite of its approval for use in children aged 10 years and older. In this study we investigated the ability of metformin to impact developmental myelination by delivering it either during myelination onset, or during a period of rapid myelination. In addition, we delivered metformin to isolated primary oligodendrocyte progenitor cells and newly-formed oligodendrocytes, and studied oligodendrocyte differentiation and myelin membrane outgrowth. We found that metformin treatment attenuated myelination in anterior white matter regions in juvenile mice compared to control littermates, despite leaving oligodendrocyte densities unchanged. Analysis of myelin ultrastructure further revealed that metformin treatment led to fewer axons being myelinated and an increase in aberrant myelin structures. Using primary oligodendrocyte cultures, we found that newly-differentiated oligodendrocytes treated with metformin developed myelin sheets that were ~ 50% smaller compared to controls, without affecting the total number of Olig2 + or MBP+ oligodendrocytes. These results suggest that during development, metformin restricts the myelinogenic capacity of individual oligodendrocytes but does not influence oligodendrocyte production. These findings have implications for the clinical use of metformin in young patients in which myelination is ongoing.