Temporal and spatial evolution of various functional neurons during demyelination induced by cuprizone

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Here we report the temporal and spatial evolution of various functional neurons during demyelination in a cuprizone (CPZ)-induced mouse model. CPZ did not significantly induce the damage of axons and neurons after 2 wk of feeding. However, after 4-6 wk of CPZ feeding, axons and neurons were markedly reduced in the cortex, posterior thalamic nuclear group, and hippo-campus. Simultaneously, the expression of TPH thorn tryptophan neurons and VGLUT1 thorn glutamate neurons was obviously decreased, and the expression of TH thorn dopaminergic neurons was slightly decreased in the tail part of the substantia nigra striatum, whereas the number of ChAT thorn cholinergic neurons was not significantly different in the brain. In the second week of feeding, CPZ caused a higher level of glutamate secretion and upregulated the expression of EAAT2 on astrocytes, which should contribute to rapid and sufficient glutamate uptake and removal. This finding reveals that astrocyte-driven glutamate reuptake protected the CNS from excitotoxicity by rapid reuptake of glutamate in 4-6 wk of CPZ feeding. At this stage, although NG2 thorn oligodendroglia progenitor cells (OPCs) were enhanced in the demyelination foci, the myelin sheath was still absent. In conclusion, we comprehensively observed the temporal and spatial evolution of various functional neurons. Our results will assist with understanding how demyelination affects neurons during CPZ-induced demyelination and provide novel information for neuro-protection in myelin regeneration and demyelinating diseases. NEW & NOTEWORTHY Our results further indicate temporal and spatial evolution of various functional neurons during the de-myelination in a cuprizone (CPZ)-induced mouse model, which mainly occur 4-6 wk after CPZ feeding. At the same time, the axonal compartment is damaged and, consequently, neuronal death occurs, while glutamate neurons are lost obviously. The astrocyte-mediated glutamate reuptake could protect the neurons from the excitatory effects of glutamate.

Automated summary

In the CPZ-induced mouse model, significant reduction of axons and neurons occurs 4-6 weeks after feeding, leading to neuronal death and loss of glutamate neurons. Astrocyte-mediated glutamate reuptake plays a protective role against excitotoxicity in the CNS.