Figure 10.

Schematic illustration of the anterograde trans-synaptic downregulation hypothesis of the spinal cholinergic pathway after CST loss or inactivation. Each panel shows the hypothesized changes in the spinal cord after loss of the CST (orange axons; action potential size represents the level of CST activity). A, In the normal condition, the cholinergic INs (green) convey corticospinal signals to motoneurons (green action potential) and, in turn, CS activation maintains the survival and function of the cholinergic INs. The microglia remain silent (not activated) as surveillance cells. B, Shortly after pyramidal tract lesion (PTx3) or 10 d of cortical inactivation, denervated cholinergic INs are less active due to the loss of CST signaling and intrinsically express more C1q (red dots). Microglia become activated and are attracted to the site and wrap and then engulf the denervated cholinergic INs, which leads to the disconnection of distal cholinergic axon terminals with the IN soma. These disconnected axons and corresponding terminal C boutons undergo Wallerian degeneration and thus show a decrease earlier than the INs. The INs that are not directly affected by PTx and their C boutons would not be expected to show C1q overexpression and would not be targets for microglial phagocytosis. C, Ten days after PTx (PTx10) or anticipated after a longer period of CST inactivation, denervated cholinergic INs and all of their terminal C boutons are fully cleared by phagocytic microglial cells. This manifests as a progressive decrease in IN numbers and C bouton density. Surviving INs are expected to maintain their C boutons or possibly to sprout more C boutons to replace those lost by the lesion/inactivation (data not shown).