Christian Krarup Group – University of Copenhagen

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Motor Control > Research > Christian Krarup Group

Christian Krarup Group

Nervelab continues the translational bridge between the department of Clinical Neurophysiology, Rigshospitalet and Copenhagen University. At the Center for Neuroscience we carry out translational studies on the relationship between electrical function and survival of myelinated motor axons within peripheral nerves.

Research

Our group has a long-standing interest in improving the outcome of peripheral nerve regeneration. By pioneering the translational use of “threshold-tracking” nerve excitability testing methods we found that regenerated human, cat and mouse myelinated motor axons show similar abnormalities in membrane excitability. Persistent alterations in voltage-dependent properties cause an imbalance between the activity-dependent Na+ influx and energy-dependent Na+ pumping mechanisms which becomes neurotoxic to regenerated nerves during repetitive stimulation. We found that this pathogenic mechanism is accentuated by aging and aggravates the progression of neuropathies associated with increase in number of nodes. We found that in mouse models of demyelinating Charcot-Marie-Tooth (CMT) disease there is also an ectopic expression of the NaV1.8 sensory-neuron-specific voltage-gated Na+ channel isoform on motor axons which enhances the neurotoxic Na+ influx (1). This raised hope that NaV1.8 could emerge as a selective therapeutic target in demyelinating neuropathies. We established a large international network for translational CMT studies, including Abbvie Inc. USA which provides novel NaV1.8 blockers with potential therapeutic use. Our current work aims to further the understanding of the link between axonal demyelination and dysregulation of axonal voltage-gated Na+ and establish its implication for activity-dependent progression of demyelinating neuropathies.

Ongoing projects:

  • Toxicity of altered voltage-gated Na+ channel expression in rodent models of demyelinating Charcot-Marie-Tooth neuropathy. Implications of repetitive impulse conduction for axonal survival.
  • Mechanisms of voltage-gated ion channel dysfunction associated with axonal regeneration/ remyelination in mice and humans. Implications of aging.
  • Development of pharmacological agents to improve conduction and survival of demyelinated fibers. Development of local anesthetics.

Specific methods:

  • Quantification of voltage-gated ion channel function in vivo using in vivo neurophysiological nerve excitability testing by” threshold-tracking” and mathematical modeling in rodents and humans.
  • Quantitative peripheral nerve morphology/immunohistochemistry. In vivo imaging using confocal laser fluorescence endomicroscopy.
  • Behavioral studies of motor and sensory function.
  • Transgenic ´mouse models of human peripheral nerve disease/ molecular studies.