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BRAIN ENERGY: Why Lactate Protects the Brain

BRAIN ENERGY: Why Lactate Protects the Brain. Johanne Egge Rinholm Brain and Muscle Energy Group lead by Linda H. Bergersen Dept of Anatomy and Centre for Molecular Biology and Neuroscience (CMBN) University of Oslo. BRAIN ENERGY: Why Lactate Protects the Brain. What is an oligodendrocyte?

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BRAIN ENERGY: Why Lactate Protects the Brain

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  1. BRAIN ENERGY: Why Lactate Protects the Brain Johanne Egge Rinholm Brain and Muscle Energy Group lead by Linda H. Bergersen Dept of Anatomy and Centre for Molecular Biology and Neuroscience (CMBN) University of Oslo

  2. BRAIN ENERGY: Why Lactate Protects the Brain • What is an oligodendrocyte? • Brain energy and lactate • Lactate uptake in oligodendrocytes • Lactate effect on myelination

  3. BRAIN ENERGY: Why Lactate Protects the Brain • What is an oligodendrocyte? • Brain energy and lactate • Lactate uptake in oligodendrocytes • Lactate effect on myelination

  4. Oligodendrocytes and White Matter GREY MATTER Neuron 1 • White matter: Myelinated nerve fibres • Oligodendrocytes are the cells that myelinate nerve fibres Myelin WHITE MATTER Grey matter Oligodendrocyte White matter Nerve fibre Coronal section from rat brain www.brainmaps.org Astrocyte GREY MATTER Neuron 2

  5. Oligodendrocytes and White Matter GREY MATTER Neuron 1 • Increase the speed of action potentials • Vulnerable to energy deprivation (Pantoni et al., 1996) Myelin WHITE MATTER Oligodendrocyte Myelinated nerve fibres Nerve fibre Astrocyte GREY MATTER Neuron 2 http://homepage.psy.utexas.edu/homepage/class/Psy332/Salinas/Cells/Cells.html

  6. Inflammation As in multiple sclerosis Loss of myelin Impaired blood flow As in cerebral palsy or stroke Oligodendrocytes do not develop or die causing lack or loss of myelin Action potentials are slower or fail Neurons die Mental and/or physical handicap

  7. BRAIN ENERGY: Why Lactate Protects the Brain • What is an oligodendrocyte? • Brain energy and lactate • Lactate uptake in oligodendrocytes • Lactate effect on myelination

  8. What is brain energy? glucose glucose • Glucose is the most important energy substrate • Must be converted to ATP, the cell’s energy currency • Lactate is an alternative energy substrate ATP glycolysis pyruvate lactate lactate ATP O2

  9. GREY MATTER Neuron 1 • Astrocytes release lactate • Neurons take up lactate • Important for neuronal survival when glucose levels are low(Pellerin et al., 1998; Brown et al., 2004; Aubert et al., 2005) • In culture: Oligodendrocytes are the most avid consumers of lactate in the CNS (Sanchez-Abarca et al., 2005) Myelin WHITE MATTER Oligodendrocyte ? Nerve fibre Astrocyte LACTATE GREY MATTER Neuron 2

  10. BRAIN ENERGY: Why Lactate Protects the Brain • What is an oligodendrocyte? • Brain energy and lactate • Lactate uptake in oligodendrocytes • Lactate effect on myelination

  11. Lac- H+ Lac- H+ Lactate transport across membranes • Happens via monocarboxylate transporters (MCTs) • MCT1, 2 and 4 located in the brain • Cotransport of 1 lactate- and 1 H+ • Produces a pH change • We can measure this with a pH-sensitive dye, BCECF (Bergersen et al., 2001; Rafiki et al., 2003)

  12. Oligodendrocytes filled with pH-dye (BCECF) through patch-pipette Application of 10mM lactate produces a pH change Lactate (and H+) is transported into cells via MCTs Lactate uptake in Oligodendrocytes

  13. MCT1 is Expressed in Myelin Electron micrographs from the cerebellar white matter

  14. BRAIN ENERGY: Why Lactate Protects the Brain • What is an oligodendrocyte? • Brain energy and lactate • Lactate uptake in oligodendrocytes • Lactate effect on myelination

  15. Myelin Nerve fibres Fluorescence intensity [Glucose] Lactate rescues myelination in low glucose • Organotypic slices cultured for 2 weeks, looked at myelination • Tested effect of glucose concentration and lactate (20 mM) on myelination Myelin(Myelin Basic Protein)Nerve fibres(Neurofilament) Oligodendrocyte lineage cells

  16. Conclusion Neuron 1 • Lactate • Energy substrate • Shuttle from one cell type to another • Oligodendrocytes can take up lactate • Important for the formation of myelin when glucose levels are low • Cerebral palsy, stroke, spinal cord injury Myelin Oligodendrocyte LACTATE Nerve fibre Astrocyte LACTATE Neuron 2

  17. Acknowledgements Linda H. Bergersen Dept of Anatomy and Centre for Molecular Biology and Neuroscience University of Oslo David Attwell Dept of Neuroscience Physiology and Phamachology University College London Nicola Hamilton Dept of Neuroscience Physiology and Phamachology University College London

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