Hippocampal Neurogenesis and Neural Circuit Formation in a Cuprizone-Induced Multiple Sclerosis Mouse Model

Abstract

Cognitive impairments are key features in multiple sclerosis (MS), a progressive disorder characterized by neuroinflammation-induced demyelination in the central nervous system. To understand the neural substrates that link demyelination to cognitive deficits in MS, we investigated hippocampal neurogenesis and synaptic connectivity of adult-born neurons, which play an essential role in cognitive function. The administration and withdrawal of the combination of cuprizone and rapamycin (Cup/Rap) in C57BL/6J male mice efficiently demyelinated and remyelinated the hippocampus, respectively. In the demyelinated hippocampus, neurogenesis was nearly absent in the dentate gyrus, which was due to inhibited proliferation of neural stem cells (NSCs). Specifically, radial glia-like type 1 NSCs were shifted from a proliferative state to a mitotically-quiescent state in the demyelinated hippocampus. In addition, dendritic spine densities of adult-born neurons were significantly decreased, indicating a reduction in synaptic connections between hippocampal newborn neurons and excitatory input neurons. Concomitant with hippocampal remyelination induced by withdrawal of Cup/Rap, proliferation of type 1 NSCs and dendritic spine densities of adult-born neurons reverted to normal in the hippocampus. Our study shows that proliferation of hippocampal NSCs and synaptic connectivity of adult-born neurons are inversely correlated with the level of demyelination, providing critical insight into hippocampal neurogenesis as a potential therapeutic target to treat cognitive deficits associated with MS.

Cuprizone Affects Hypothermia-Induced Neuroprotection and Enhanced Neuroblast Differentiation in the Gerbil Hippocampus after Ischemia

“…The CPZ group showed a significant reduction in cell proliferation and neuroblast differentiation in the dentate gyrus compared to that in the CTL group. This result is in agreement with previous studies showing that neurogenesis is decreased in cuprizone-treated mice [25,66,67]. We also observed that transient forebrain ischemia significantly increased cell proliferation and neuroblast differentiation in the dentate gyrus of the hippocampus, consistent with previous studies [68][69][70][71].…”

DCX+ neuronal progenitors contribute to new oligodendrocytes during remyelination in the hippocampus

“…In contrast to our results showing no significant differences in the numbers of DCX + cells, reduced numbers of DCX + NPCs were reported in a 4-week 47 , and a 6-week 48 cuprizone model. Additionally, and Zhang and collaborators described a reversible loss of DCX staining after a 6-week treatment with 0.3% cuprizone alone or in combination with rapamycin 49 . These, seemingly, contradictory findings might be in part explained by differences in analysis methods and in cuprizone models, but this would need to be further investigated.…”

Ferroptosis Mediates Cuprizone-Induced Loss of Oligodendrocytes and Demyelination

“…Cuprizone (CZ) is a copper chelator that causes demyelination in the CNS, noted particularly in the corpus callosum (CC) but also seen in other CNS regions (Gudi et al, 2009;Kipp et al, 2009;Koutsoudaki et al, 2009;Steelman et al, 2012;McMurran et al, 2019). It is widely used as a model to study experimental strategies to prevent myelin loss or promote remyelination (Mason et al, 2000;Bai et al, 2016;Karamita et al, 2017;Mullin et al, 2017;Laflamme et al, 2018) and neuronal plasticity (Zhang et al, 2020) in the context of multiple sclerosis (MS). How chelating copper induces oligodendrocyte (OL) death is not understood (McMurran et al, 2019), despite extensive work on its use as a model to study remyelination.…”