Abstract
Synapse elimination in the adult central nervous system can be modelled by axotomy of spinal motoneurons which triggers removal of synapses from the cell surface of lesioned motoneurons by processes that remain elusive. Proposed candidate mechanisms are removal of synapses by reactive microglia and astrocytes, based on the remarkable activation of these cell types in the vicinity of motoneurons following axon lesion, and/or decreased expression of synaptic adhesion molecules in lesioned motoneurons. In the present study, we investigated glia activation and adhesion molecule expression in motoneurons in two mouse strains with deviant patterns of synapse elimination following axotomy. Mice deficient in complement protein C3 display a markedly reduced loss of synapses from axotomized motoneurons, whereas mice with impaired function of major histocompatibility complex (MHC) class Ia display an augmented degree of stripping after axotomy. Activation of microglia and astrocytes was assessed by semiquantative immunohistochemistry for Iba 1 (microglia) and GFAP (astrocytes), while expression of synaptic adhesion molecules was determined by in situ hybridization. In spite of the fact that the two mouse strains display very different degrees of synapse elimination, no differences in terms of glial activation or in the downregulation of the studied adhesion molecules (SynCAM1, neuroligin-2,-3 and netrin G-2 ligand) could be detected. We conclude that neither glia activation nor downregulation of synaptic adhesion molecules are correlated to the different extent of the synaptic stripping in the two studied strains. Instead the magnitude of the stripping event is most likely a consequence of a precise molecular signaling, which at least in part is mediated by immune molecules.
Highlights
Peripheral axotomy triggers the removal of synapses from lesioned motoneurons by mechanisms that still remain elusive [1,2,3,4,5]
We here use two mouse strains with increased (Kb2/2Db2/2; [17]) or decreased (C32/2; [18]) synaptic stripping of axotomized motoneurons to investigate whether the observed differences in the degree of synaptic removal were paralleled by changes in two suggested possible basic events underlying synapse removal [1]; activation of glial cells and/or differences in the regulation of synaptic adhesion molecules in lesioned motoneurons
These mouse strains, which have very different phenotypes in terms of synaptic stripping, displayed a similar activation of both microglia and astrocytes one week after sciatic nerve lesion, which in turn was very similar to that seen in wild type (WT) animals
Summary
Peripheral axotomy triggers the removal of synapses from lesioned motoneurons by mechanisms that still remain elusive [1,2,3,4,5]. Subsequent studies have shown that pharmacological or genetical ablation of the injury-induced proliferation of microglia does not affect synaptic stripping of axotomized motoneurons [1,7,8], leading to the suggestion that astrocytes might be involved in the synaptic stripping process. Another possible mechanism for the reduced number of synaptic inputs to axotomized motoneurons is an attenuated adhesiveness between the motoneurons and presynaptic terminals [1]. These molecules are all downregulated in axotomized motoneurons before the loss of synapses and their expression return as new synapses are formed [6,15,16]
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