Synaptic stripping and beyond: Microglia or astrocytes?

About forty years ago, Blinzinger and Kreutzberg first reported that perineuronal microglia actively engaged in the displacement of synaptic boutons from the surface of regenerating motoneurons. This phenomenon is called synaptic stripping, which is assumed to help survival of axotomized neurons via reduction of synaptic inputs. Although the synaptic stripping hypothesis has long been accepted, it might tie a horse to the rear side of a cart. Particularly, the protective role of microglia has been contradicted by several studies. For instance, our recent study revealed that the extension of microglial process was preceded by the reduction of synaptic activities after nerve injury. Extracellular nucleotides including ATP and its major metabolite adenosine were found to be responsible for the reduced synaptic activities before microglial apposition. Together, it is reasonable to suppose that some components other than microglia, i.e., astrocyte and oligodendrocyte, might be responsible for reduction in synaptic inputs after axotomy. In the subsequent study, we investigated the axotomy-induced changes in astrocytic and microglial coverage of motoneuron synaptic circumference in mice and rats. Because peripheral nerve axotomy induces apoptotic cell death in mice but not in rats, the comparative analysis might give some key to understanding the mechanisms underlying cell fate decision. Our results showed that the interposition of synapses by astrocytes but not by microglia may primarily mediate neuroprotective effects through the reduction of synaptic inputs. We highlight here the current understanding of the differential involvement of microglia and astrocytes in synaptic stripping and cell fate decision in the axotomy paradigm.