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.SIGNIFICANCE STATEMENT To identify the neural substrates that mediate cognitive dysfunctions associated with a majority of MS patients, we investigated hippocampal neurogenesis and structural development of adult-born neurons using a Cup/Rap model, which recapitulates the hippocampal demyelination that occurs in MS patients. A shift of NSCs from a proliferatively-active state to mitotically-quiescent state dramatically decreased neurogenesis in the demyelinated hippocampus. Formation of dendritic spines on newborn neurons was also impaired following demyelination. Interestingly, the altered neurogenesis and synaptic connectivity of newborn neurons were reversed to normal levels during remyelination. Thus, our study revealed reversible genesis and synaptic connectivity of adult-born neurons between the demyelinated and remyelinated hippocampus, suggesting hippocampal neurogenesis as a potential target to normalize cognitive impairments in MS patients.