Title:
Control of Local Protein Synthesis and Initial Events in Myelination by Action Potentials
Hiroaki WAKE
Nervous System Development & Plasticity Section National Institutes of Health
Abstract:
Neural activity may stimulate myelin formation, the electrical insulation on nerve fibers, in association with learning and postnatal experience. Oligodendrocytes, the myelinating glia of the CNS, are morphologically complex cells that are capable of myelinating multiple axons independently from many different cellular extensions and induce rapid conduction of electrical impulses in the vertebrate brain ( 1, 2 ) . Myelin formation is essential for information processing because myelin increases conduction velocity at least 50 times ( 3 ) . Stimulating myelination as a result of impulse activity in axons could enable myelin to be regulated by environmental experience, which could contribute to information processing and learning in the brain. We have shown that oligodendrocytes, the myelinating glia of the CNS, exhibit elevated Ca2+ responses in their fine processes and cell soma, in response to action-potential (AP) firing in axons. These Ca2+ responses in oligodendrocytes exhibit differential kinetics, reflective of a specific intracellular response to electrical-activity evoked neurotransmitter release from axons. Inhibition of the Ca2+responses in oligodendrocyte processes significantly inhibits myelin formation without affecting oligodendrocyte differentiation. We have demonstrated that elevated Ca2+ responses in oligodendrocyte processes promotes the turnover of cholesterol rich domains as visualized by a pH sensitive GFP fused with transferrin receptor ( 4 ) . We have visualized myelin basic protein (MBP) local translation using a photo-convertible GFP fused to the 3’UTR of MBP. Using this system we have shown that de novo translation of mRNA for MBP, the major constituent of myelin sheaths occurs in direct response to electrically active axons. We also demonstrate that local translation of MBP mRNA in oligodendrocyte processes is initialized myelin formation at the site of connection between oligodendrocytes and axons. These findings provide new insight into how myelination, and thus conduction velocity and function of neural circuits, can be regulated by nervous system activity ( 5 ) .
References:
1. K. A. Nave, Nature 468 , 244 (Nov 11, 2010).
2. B. Emery, Science 330 , 779 (Nov 5, 2010).
3. F. K. Sanders, D. Whitteridge, J Physiol 105 , 152 (Sep 18, 1946).
4. M. J. Kennedy, I. G. Davison, C. G. Robinson, M. D. Ehlers, Cell 141 , 524 (Apr 30, 2010).
5. H. Wake, P. R. Lee, R. D. Fields, Science 333 , 1647 (Sep 16, 2011).
