Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length.

Nicola B Hamilton,William D Richardson,Moritz Matthey,David Attwell,Louise Whiteley,Ragnhildur Káradóttir,I Lorena Arancibia-Carcamo,Laura E Clarke,Eleni Kougioumtzidou,Linda H Bergersen

doi:10.1002/glia.23093

Abstract

Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10‐positive oligodendrocytes, that endogenously released GABA, acting on GABAA receptors, greatly reduces the number of oligodendrocyte lineage cells. The decrease in oligodendrocyte number correlates with a reduction in the amount of myelination but also an increase in internode length, a parameter previously thought to be set by the axon diameter or to be a property intrinsic to oligodendrocytes. Importantly, while TTX block of neuronal activity had no effect on oligodendrocyte lineage cell number when applied alone, it was able to completely abolish the effect of blocking GABAA receptors, suggesting that control of myelination by endogenous GABA may require a permissive factor to be released from axons. In contrast, block of AMPA/KA receptors had no effect on oligodendrocyte lineage cell number or myelination. These results imply that, during development, GABA can act as a local environmental cue to control myelination and thus influence the conduction velocity of action potentials within the CNS. GLIA 2017;65:309–321

Highlights

By speeding action potential conduction, myelination of CNS axons by oligodendrocytes increases the brain’s cognitive abilities
Our data reveal that the neurotransmitter GABA exercises a major influence on the number of oligodendrocyte lineage cells in situ in cerebral cortical slices
Blocking the effects of GABA on GABAA receptors nearly doubled the number of oligodendrocyte lineage cells (Fig. 2A,B), increased myelination (Fig. 4G,H) and decreased internode length (Fig. 5G,H)

Summary

Introduction

By speeding action potential conduction, myelination of CNS axons by oligodendrocytes increases the brain’s cognitive abilities. An adjustment of myelin thickness or internode length may be used to tune the conduction speed of myelinated axons (Fields, 2008; Ullen, 2009). This can promote synchronous neuronal firing (Lang and Rosenbluth, 2003; Sugihara et al, 1993), make impulse propagation time less dependent on the spatial trajectory of the axon transmitting information between areas (Salami et al, 2003), or adjust propagation delays to mediate sound localization (Ford et al, 2015; Jeffress, 1948; McAlpine and Grothe, 2003; Seidl et al, 2010).

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