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Using zebrafish to investigate and interfere with activity dependent myelination in vivo.


Founded as repatriation grant by the ministry for innovation, science and research in North-Rhine-Westphalia the following work is planed in cooperation with the University of Bonn at the Anatomical Institute.

White matter "myelin" disorders are the cause of many common neurological diseases like multiple sclerosis (MS), Charcot-Marie-Tooth (CMT) or Pelizaeus-Merzbacher disease. Recently also a wide range of psychiatric disorders like schizophrenia, bipolar disorder, autism or chronic depression have been associated to defects in CNS white matter (Fields, 2008); showing abnormalities in expression of many genes involved in the myelination process. Furthermore it has been shown that up to 25% of prematurely born infants with low birth weight (<1.500 g) are developing a periventricular white matter injury (PWMI) due to altered oligodendrocyte development. This PWMI is often associated with motor and cognitive deficits observed later in such infants. Failure of oligodendrocyte differentiation and re-myelination is also a major reason for permanent paralysis after spinal cord injury. 

Despite this huge involvement of oligodendrocyte CNS myelination in health and disease there is still a great amount of ambiguity when it comes to questions about various factors that induce oligodendrocytes to ensure proper initial myelination, re-myelination or even fine tuning of myelination providing CNS plasticity for learning and memory. A lot of the work that has been done so far focuses on autoimmune reactions against the myelin sheath and on cell signaling factors that are involved in oligodendrocyte proliferation, outgrowth and differentiation. So far most of this work has been done in vitro and little is known about how neuronal activity and activity in surrounding glia tissue, like changes in the cells membrane potential, is additionally influencing the myelination process.   

To get a better understanding of the influence that various activity of different cells has on the myelination process we want to simultaneously monitor cell activity and myelination in zebrafish in vivo. Zebrafish are commonly used as a vertebrate model organism of neural development as well as myelination (Buckley et al., 2008). The fundamental properties of myelin are widely shared among vertebrates, and the zebrafish has emerged as a powerful system to study the myelination process in vivo using fluorescent proteins (Yoshida and Macklin, 2005). Zebrafish are also very well suited for genetic manipulations, over-expression studies, morpholino knock-down experiments, as well as targeted knock-out / knock-in fish-line generation using the recently described zinc-finger technique. A large number of mutant fish lines including many with myelination phenotypes are freely available from several screening projects. Furthermore the zebrafish larvae’s transparency and the existence of various albino lines make it an ideal model for all kinds of non-invasive in vivo imaging.









Several neurotransmitter receptors have been found in oligodendrocytes, for example application of glutamate and even GABA - in contrary to conventional neurons - leads to their depolarization. Like neurons and astrocytes, oligodendrocytes also increase their internal Ca2+ level through neuro-transmitter receptors and voltage gated channels (Kirischuk et al., 1995), which again can get activated by an increase in extracellular K+ concen-trations. Monitoring internal Ca2+ concentrations with the fluorescent GCaMP reporter or variants of it (Dreosti et al., 2009) will be one way of accessing activity levels in oligodendrocytes and other surrounding glia or neuronal cells by in vivo 2-photon imaging techniques. The intracellular Ca2+ concentration plays an important role in processes such as induction of synaptic plasticity, pathophysiology of several diseases, other intracellular signaling and transmitter release. Transmitter release again, as another form of cell activity, can be monitored very precisely using sypHy or variants of it (Granseth et al., 2006; Odermatt et al., 2012). The possibility of generating mosaic zebrafish expressing different fluorescent reporters for myelination and / or cell activity in different cells by cell transplantations from different transgenic fish lines (Carmany and Moens, 2006) will provide me with very powerful tools to investigate their interaction in vivo. In the long term we hope to even be able to remotely manipulate the cells activity by expressing light gated channels like channelrhodopsin and halorhodopsin (Zhang et al., 2007) in these cells.

Oligodendrocytes remove K+ from the extracellular space through inward rectifier K+ channels and connexin channels (Menichella et al., 2006; Odermatt et al., 2003). When the oligodendrocyte is depolarized, K+ influx into the oligodendrocyte is reduced because the conductance through these channels is decreased, and so the extracellular K+ concentration significantly increases since the extracellular space is small. Thus, neuronal action potentials might be more easily evoked at the nodes, and therefore conduction velocity increases by depolarization of the oligodendrocytes. In this case oligodendrocytes do not only influence the axons that they enwrap themself but also those just passing through their field of action (Yamazaki et al., 2010).

In conclusion it seems that myelination and oligodendrocyte function in health and disease relay on a very complex interplay of many different factors of which one certainly is the activity level of the cells involved themself. A better understanding of these activity dependent regulations in vivo should certainly help getting new insights into the process of myelination.


References / Selected Readings:

  • Buckley et al., 2008: Temporal Dynamics of Myelination in the Zebrafish Spinal Cord; Glia 58:802-812
  • Carmany and Moens, 2006: Modern mosaic analysis in the zebrafish; Methods 39:228-238
  • Dreosti et al., 2009: A genetically encoded reporter of synaptic activity in vivo; Nature Methods 12:883-889
  • Fields, 2008: White matter in learning, cognition and psychiatric disorders; Trends in Neuroscience 31:361-370
  • Granseth et al., 2006: Clathrin-Mediated Endocytosis is the Dominant Mechanism of Vesicle Retrieval at Hippocampal Synapses; Neuron 51:773-786
  • Kirischuk et al., 1995: Subcellular heterogeneity of voltage-gated Ca2+ channels in cells of the oligodendrocyte lineage; Glia 13:1-12
  • Menichella et al., 2006: Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of K+; J. Neurosci. 26:10984-10991
  • Odermatt et al., 2003: Connexin 47 deficient mice with EGFP reporter reveal oligodendrocytic expression of Cx47; J. Neurosci. 23:4549-4559
  • Odermatt et al., 2012: Encoding of luminance and contrast by linear and non-linear synapses in the retina; Neuron 73:758-773
  • Yamazaki et al., 2010: Oligodendrocytes: Facilitating Axonal Conduction by more than myelination; The Neuroscientist 16:11-18
  • Yoshida and Macklin, 2005: Oligodendrocyte development and myelination in GFP-transgenic zebrafish; J. Neurosci Res. 81:1-8
  • Zhang et al., 2007: Circuit-breakers: optical technologies for probing neural signals and systems; Nature Rev. Neurosci. 8:577-581