Suminaite, D. | Search bioRxiv

bioRxiv2023

Importin 13-dependent Axon Diameter Growth Regulates Conduction Speeds along Myelinated CNS Axons

Central nervous system neurons have axons that vary over 100-fold in diameter. This diversity contributes to the regulation of myelination and conduction velocity along axons, which is critical for proper nervous system function. Despite this importance, technical challenges have limited our understanding of mechanisms controlling axon diameter growth, preventing systematic dissection of how manipulating diameter affects conduction along individual axons. Here, we establish zebrafish as system to investigate the regulation of axon diameter and axonal conduction in vivo. We identify a role for importin 13b specifically in axon diameter growth, that is independent of axonal length and overall cell size. Impairment of diameter growth along individual myelinated axons reduced conduction velocity in proportion to the diameter, but had no effect on the precision of action potential propagation or ability to fire at high frequencies. This work highlights an axon diameter-specific mechanism of growth that regulates conduction speeds along myelinated axons.

neuroscience↗

bioRxiv2021

Central nervous system hypomyelination disrupts axonal conduction and behaviour in larval zebrafish

Myelination is essential for central nervous system (CNS) formation, health and function. As a model organism, larval zebrafish have been extensively employed to investigate the molecular and cellular basis of CNS myelination, due to their genetic tractability and suitability for non-invasive live cell imaging. However, it has not been assessed to what extent CNS myelination affects neural circuit function in zebrafish larvae, prohibiting the integration of molecular and cellular analyses of myelination with concomitant network maturation. To test whether larval zebrafish might serve as a suitable platform with which to study the effects of CNS myelination and its dysregulation on circuit function, we generated zebrafish myelin regulatory factor (myrf) mutants with CNS-specific hypomyelination and investigated how this affected their axonal conduction properties and behaviour. We found that myrf mutant larvae exhibited increased latency to perform startle responses following defined acoustic stimuli. Furthermore, we found that hypomyelinated animals often selected an impaired response to acoustic stimuli, exhibiting a bias towards reorientation behaviour instead of the stimulus-appropriate startle response. To begin to study how myelination affected the underlying circuitry, we established electrophysiological protocols to assess various conduction properties along single axons. We found that the hypomyelinated myrf mutants exhibited reduced action potential conduction velocity and an impaired ability to sustain high frequency action potential firing. This study indicates that larval zebrafish can be used to bridge molecular and cellular investigation of CNS myelination with multiscale assessment of neural circuit function.

neuroscience↗