Pre- and postsynaptic changes at the axo-glial synapses in white matter during de- and remyelination

• Applicant: Dr. Friederike Pfeiffer
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 272985102

After a demyelinating event, as it occurs during certain neurologic diseases like Muliple Sclerosis (MS), mature oligodendrocytes are lost. Remyelination sometimes occurs and prevents axons from degeneration, if oligodendrocyte precursor cells (OPCs) are present in or migrating to the region of demyelination and differentiate into myelinating oligodendrocytes. Different molecules and different types of cellular interactions are known to play a role in OPC-axon recognition and remyelination, yet one of the least investigated factors with this respect is electrical activity in axons. Nevertheless, electrical properties of axons are likely to be involved in the process of remyelination, since it is known from developmental myelination, that neurons release neurotransmitter at contact-sites with OPCs, that OPCs express AMPA receptors to detect axonal signals and that these axo-glial synapses are lost as OPCs mature into oligodendrocytes exerting myelination. Yet, it should be kept in mind that under pathological conditions such as demyelination, axons re-arrange and re-express different sodium channel subunits in order to restore the ability to conduct action potentials, which may in turn affect the release of neurotransmitter towards OPCs.Since remyelination has many similarities with developmental myelination, I hypothesize that axons and OPCs in the demyelinated white matter region fail to fully re-establish correct patterns of synaptic signaling that usually take place during developmental demyelination. This results in abnormal/incomplete/delayed remyelination. To investigate these questions, in vivo models of de- and remyelination in transgenic mice will be combined with in situ electrophysiology, immunohistochemistry, and confocal laser scanning microscopy. On the one hand, changes at the pre-synaptic site will be addressed, e.g. glutamate release by the axon during remyelination and also the changes in axonal properties upon altered sodium channel expression. On the other hand, changes in the electrophysiological properties of OPCs and oligodendrocytes at the postsynaptic site are addressed, in particular alterations in AMPA receptor expression and AMPA subunit composition (determining calcium-permeability).The expected results will help to understand the role of axo-glial communication during remyelination, which is of great importance for the development of new therapies that aim at remyelination and axon preservation in neurodegenerative diseases. In addition, differences between axo-glial synapses during development and during remyelination under pathological conditions in the adult central nervous system will be described.

• DFG Programme: Research Grants