SynCAM1 expression correlates with restoration of central synapses on spinal motoneurons after two different models of peripheral nerve injury

Abstract

SynCAM1 and neuroligins (NLGs) are adhesion molecules that govern synapse formation in vitro. In vivo, the molecules are expressed during synaptogenesis, and altered NLG function is linked to synapse dysfunction in autism. Less is known about SynCAM1 and NLGs in adult synapse remodeling. CNS synapse elimination occurs after peripheral nerve injury, which causes a transient decrease in synapse number on spinal motoneurons. Here we have studied the expression of SynCAM1 and NLGs in relation to changes in synaptic covering on spinal motoneurons. We performed sciatic nerve transection (SNT) or crush (SNC), axotomy models that result in poor or good conditions for axon regeneration, respectively. The two lesions resulted in similar synapse elimination and in poor (SNT) and good (SNC) return of synapses after 70 days. Functional recovery was good after SNC but absent after SNT. SynCAM1 mRNA decreased after 14 days in both models and was restored 70 days after SNC, but not after SNT. NLG2 and -3 mRNAs decreased to a smaller degree after SNC than after SNT. Synaptophysin immunoreactivity correlated with SynCAM1 mRNA 70 days after SNT and NLG2 mRNA 70 days after SNC. Surprisingly, an inverse correlation was seen between NLG3 mRNA and Vglut2, a marker for excitatory synapses, 70 days after SNT. We conclude that 1) SynCAM1 mRNA levels seem to reflect the loss and restoration of synapses on motoneurons, 2) down-regulation of NLGs is not a prerequisite for synapse elimination, and 3) expression of SynCAM1 and NLGs is regulated by different mechanisms during regeneration.

Netrin G-2 ligand mRNA is downregulated in spinal motoneurons after sciatic nerve lesion

“…1g-i, l). From earlier studies [8], we know that the maximal extent of synaptic stripping is reached at 14 days after axotomy, a time point when NGL-2 mRNA levels have started increasing.…”

“…For instance, SynCAM and neuroligins (NLGs) are able to induce synapse formation in various assays and NLG-deficient mice display altered synaptic function [3][4][5][6][7]. Recently we showed that axotomized spinal motoneurons change their expression of SynCAM1, and NLG-2 and NLG-3 during synaptic detachment and restoration after peripheral nerve injury [8]. Whether SynCAM1 and NLGs are the only synaptic adhesion molecules affected by axotomy in spinal motoneurons is not known.…”

“…Both SNT and SNC result in axotomy, but only in SNT are the motoneuron axons initially completely separated from the distal stump of the nerve, which provide guidance and trophic support in regenerating axons. From earlier studies, we know that SNT results in a variable restoration of synapses, whereas SNC results in a complete recovery in terms of number of synapses and function [8].…”

The Effects of Exercise on Synaptic Stripping Require Androgen Receptor Signaling

“…Initial observations [33], [34], [35], [36] were used to suggest that processes of reactive astrocytes and/or microglia, which proliferate and surround axotomized motoneurons, might play an important role, but based on the results of more recent studies [37], a shift in attention to axotomy induced changes in the motoneurons has occurred. In particular, the decline in production of cell adhesion molecules by axotomized motoneurons has been shown to precede the actual withdrawal of synapses [20], [36], [38], [39], suggesting that, in intact animals, these molecules are part of an active, retrograde signaling mechanism that promotes synapse retention. In addition, immune system-related molecules, such as the major histocompatibility complex (MHC) class I molecules [39] and members of the complement family [40] have been associated with synaptic withdrawal.…”

Retrograde response in axotomized motoneurons: Nitric oxide as a key player in triggering reversion toward a dedifferentiated phenotype

“…It is conceivable, therefore, to postulate that the breakage of this adhesive binding could be a preliminary step that antecedes synapse disassembly in axotomized motoneurons. In a series of related studies, it has been found that axotomy induces rapid down-regulation of the mRNAs encoding for the CAMs neuroligin-2, neuroligin-3, netrin G-2 ligand, netrin G-3 ligand, and SynCAM1 in motoneurons, as well as a more gradual decrease in the level of PSD-95 mRNA expression (Zelano et al, 2007(Zelano et al, , 2009Berg et al, 2010). The long-term expression analysis further showed that these changes were reversed following regeneration, in parallel with the restoration of afferent synaptic inputs to the motoneurons.…”