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Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination.

Sahel A, Ortiz FC, Kerninon C, Maldonado PP, Angulo MC, Nait-Oumesmar B - Front Cell Neurosci (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U1127, Institut du Cerveau et de la Moelle Epinière Paris, France ; Université Paris 6, Sorbonne Paris Cité, UMR-S1127 Paris, France ; Centre National de la Recherche Scientifique UMR 7225 Paris, France.

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.

No MeSH data available.


Related in: MedlinePlus

Voltage-independent K+ currents and Na+ currents did not change in white matter OPCs following demyelination. (A–C) Capacitance, K+ and Na+ current densities of OPCs recorded in control conditions and in lesions at different dpi. K+ and Na+ current densities were calculated at −120 mV and −10 mV, respectively (see Materials and Methods). Note that the scale is 10 times smaller for K+ than for Na+ current densities. ns, not significant.
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Figure 3: Voltage-independent K+ currents and Na+ currents did not change in white matter OPCs following demyelination. (A–C) Capacitance, K+ and Na+ current densities of OPCs recorded in control conditions and in lesions at different dpi. K+ and Na+ current densities were calculated at −120 mV and −10 mV, respectively (see Materials and Methods). Note that the scale is 10 times smaller for K+ than for Na+ current densities. ns, not significant.

Mentions: In order to reveal any potential upregulation of voltage-independent K+ conductances in OPCs after demyelination as reported during gray matter development (Maldonado et al., 2013) and to test for potential modifications on Na+ channel-mediated current amplitudes in reactived OPCs, we compared the capacitance, K+ and Na+ current densities between controls and at 4, 7, and 14 dpi (Figures 3A–C). No differences were detected in lesions with respect to controls and at any time point after LPC injection. Overall, our results indicate that appropriate transgenic lines are needed to ensure OPC, oligodendrocyte and microglia identification under pathological conditions and that Na+ and voltage-independent K+ conductances of OPCs are not affected by LPC-induced lesions.


Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination.

Sahel A, Ortiz FC, Kerninon C, Maldonado PP, Angulo MC, Nait-Oumesmar B - Front Cell Neurosci (2015)

Voltage-independent K+ currents and Na+ currents did not change in white matter OPCs following demyelination. (A–C) Capacitance, K+ and Na+ current densities of OPCs recorded in control conditions and in lesions at different dpi. K+ and Na+ current densities were calculated at −120 mV and −10 mV, respectively (see Materials and Methods). Note that the scale is 10 times smaller for K+ than for Na+ current densities. ns, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362325&req=5

Figure 3: Voltage-independent K+ currents and Na+ currents did not change in white matter OPCs following demyelination. (A–C) Capacitance, K+ and Na+ current densities of OPCs recorded in control conditions and in lesions at different dpi. K+ and Na+ current densities were calculated at −120 mV and −10 mV, respectively (see Materials and Methods). Note that the scale is 10 times smaller for K+ than for Na+ current densities. ns, not significant.
Mentions: In order to reveal any potential upregulation of voltage-independent K+ conductances in OPCs after demyelination as reported during gray matter development (Maldonado et al., 2013) and to test for potential modifications on Na+ channel-mediated current amplitudes in reactived OPCs, we compared the capacitance, K+ and Na+ current densities between controls and at 4, 7, and 14 dpi (Figures 3A–C). No differences were detected in lesions with respect to controls and at any time point after LPC injection. Overall, our results indicate that appropriate transgenic lines are needed to ensure OPC, oligodendrocyte and microglia identification under pathological conditions and that Na+ and voltage-independent K+ conductances of OPCs are not affected by LPC-induced lesions.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U1127, Institut du Cerveau et de la Moelle Epinière Paris, France ; Université Paris 6, Sorbonne Paris Cité, UMR-S1127 Paris, France ; Centre National de la Recherche Scientifique UMR 7225 Paris, France.

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.

No MeSH data available.


Related in: MedlinePlus