Background: The re-formation of functionally meaningful circuits after injury requires removal of excessive synapses.
Hypothesis: The decision which synapses to remove is a central checkpoint for neuronal recovery that is critically regulated by the glial cells that remove these synapses.
Strategy: We will combine structural and functional mapping of spinal circuits with molecular profiling and targeted genetic manipulation to reveal the mechanisms and consequences of glia-mediated synapse removal after spinal cord injury.
To date there is no therapy that prevents the devastating consequences of spinal cord injury. Current preclinical approaches mainly focus on initiating the regeneration of severed axons. However, those axons almost always fail to reach their targets and thus are unlikely to be major contributors to functional recovery. While transected axons fail to grow long distance, they can extend new collaterals into the local grey matter. The successful integration of these collaterals into preserved neuronal circuits - so called circuit rewiring - is the basis of endogenous functional recovery. The formation of intraspinal detour circuits by the injured corticospinal tract (CST) is a functionally important paradigm that we and others have used to study and mechanistically dissect circuit rewiring in the adult central nervous system (CNS). The rewiring of the injured CST proceeds in two steps: First, emerging CST collaterals enter the grey matter of the cervical spinal cord – far remote from the thoracic lesion site - and form excessive contacts with a range of spinal interneurons. This is followed by a refinement phase, during which functionally meaningful connections are maintained while those that do not contribute to recovery are removed. The crucial process that determines which synapses to maintain and which to remove has emerged as a critical checkpoint for the re-formation of functionally meaningful detour circuits. As glial cells are important regulators that sculpt developing circuits by synapse removal, we now want to determine if and how these cells also shape the remodelling of the injured adult CNS. Identifying the cellular and molecular checkpoints that regulate glial sculpting of rewiring circuits will not only provide important insights into a relatively unexplored aspect of neuronal remodelling but will also provide the basis for therapeutic strategies to correct “aberrant” glial responses e.g. in the aged or chronically inflamed CNS.