Friend or foe? The AMPK signaling pathway during developmental myelination

Myelination is a highly energy-intensive process. Despite this, how oligodendroglial cells regulate energy production and usage remains poorly understood. A candidate regulator of oligodendroglial energetics is AMPK, a Ser/Thr kinase that both responds to cell energy levels and regulates energy production, thus acting as a metabolic sensor. AMPK is activated endogenously when ATP levels dip, for instance in fasting or exercise, but AMPK activity can also be manipulated pharmacologically, for instance using the diabetes drug metformin. In adult mice, metformin has recently been found to both activate oligodendroglial AMPK and enhance remyelination following myelin damage , whereas in aged mice, which typically show limited myelin repair, metformin causes an even more pronounced increase in remyelination. These studies have led to the prediction that metformin is a desirable candidate for the treatment of demyelinating diseases, and several clinical trials are now underway for MS. However, our preliminary studies suggest that AMPK activation via metformin treatment during postnatal development may delay or suppress myelination. And, despite the growing interest in metformin and other AMPK activators in neurological diseases, AMPK’s ability to regulate oligodendroglial dynamics and myelination during development remains unresolved. For instance, a mouse knockout of the AMPK regulatory subunit in neural stem cells led to profound alterations in neural progenitor cell proliferation and neural cell survival, with the resulting brains being substantially smaller and severely hypomyelinated. However, given the gross alterations to overall brain development, it was not clear whether AMPK loss in oligodendroglia themselves contributed to the hypomyelination. In this proposal we test the hypothesis that regulated oligodendroglial AMPK signaling is essential for correctly timed myelination, and will assess the prediction that enhanced AMPK signaling during the high metabolic demand of developmental myelination will suppress myelination. In Aim 1, mice will be treated with metformin during distinct temporal windows spanning early, mid, and late developmental myelination, followed by an assessment of the steps in oligodendrocyte development (OPC proliferation, survival differentiation) necessary for appropriate myelination and of the resulting myelin itself. In Aim 2, conditional knockout mice, AMPKa1f/fl; PDGFRa-Cre mice that lack the predominant AMPK catalytic subunit, will be used to determine the role of AMPK in oligodendrocyte lineage dynamics and myelination, as in Aim 1. In Aim 3, isolated mouse OPCs and oligodendrocytes will be used to determine transcriptome differences in response to metformin (AMPK activation) or in AMPKa1f/fl; PDGFRa-Cre+ cells (AMPK LOF), followed by pathway analysis. These studies will fill the knowledge gap on the role of AMPK in oligodendrocyte development and myelination, as well as investigate the translational impact of metformin on developmental myelination.