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 Coronal section from rat brain White matter: Myelinated nerve fibres Oligodendrocytes are the cells that myelinate nerve fibres Grey matter White matter GREY MATTER WHITE MATTER GREY MATTER Astrocyte Nerve fibre Neuron 1 Myelin Neuron 2 Oligodendrocyte

5 Oligodendrocytes and White Matter Increase the speed of action potentials Vulnerable to energy deprivation (Pantoni et al., 1996) Myelinated nerve fibres GREY MATTER WHITE MATTER GREY MATTER Astrocyte Nerve fibre Neuron 1 Myelin Neuron 2 Oligodendrocyte

6 Loss of myelin As in cerebral palsy or stroke Impaired blood flow Inflammation As in multiple sclerosis 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 is the most important energy substrate glucose glycolysis ATP Must be converted to ATP, the cell s energy currency ATP pyruvate lactate lactate Lactate is an alternative energy substrate O 2

9 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) GREY MATTER WHITE MATTER GREY MATTER Astrocyte? LACTATE Myelin Nerve fibre Neuron 1 Neuron 2 Oligodendrocyte

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 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 phsensitive dye, BCECF Lac - Lac - H + H + (Bergersen et al., 2001; Rafiki et al., 2003)

12 Lactate uptake in Oligodendrocytes 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

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 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 Fluorescence intensity Myelin Nerve fibres Myelin (Myelin Basic Protein) Nerve fibres (Neurofilament) Oligodendrocyte lineage cells [Glucose]

16 Conclusion Lactate Neuron 1 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 LACTATE Myelin Nerve fibre Oligodendrocyte Cerebral palsy, stroke, spinal cord injury 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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