Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination

Abstract

Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders.

Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease

“…Remyelination is carried out by OPCs that migrate to the site of damage, proliferate, differentiate and wrap their processes around the demyelinated axons to form a new myelin sheath (see reviews in this issue by Chamberlain et al, 2016;Tognatta & Miller 2016). It has been shown recently that demyelinated axons upregulate presynaptic proteins in the ethidium bromide lesion model in rats (Gautier et al, 2015), in lysolecithin lesions in mice (Etxeberria et al, 2010;Sahel et al, 2015) and in MS patients, and are able to form synapses with recruited OPCs (Gautier et al, 2015;Sahel et al, 2015). These OPCs express AMPA/kainate receptors and, at later stages, also NMDA receptors (Gautier et al, 2015).…”

Bad wrap: Myelin and myelin plasticity in health and disease

“…The functional role of neuron to OPC synapses (Bergles et al, ) remains enigmatic (Etxeberria et al, ; Sahel et al, ). While deletion of the NR1 NMDA receptor subunit in oligodendrocytes in the EAE model of MS had no effect on either the severity or progression of the disease (Guo et al, ), NMDA signaling may still play an important role in myelin regeneration.…”

Lineage, fate, and fate potential of NG2-glia

“…More recent cre/loxP fate mapping studies show that NG2 cells in the adult white matter contribute to oligodendrocyte and myelin repair (Sahel et al, 2015). In the spinal cord, when demyelination is accompanied by compromised astrocytes, NG2 cells generate not only oligodendrocytes but also Schwann cells that contribute to myelin repair (Zawadzka et al, 2010).…”