Astrocytes: Lessons Learned from the Cuprizone Model

A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at both the molecular and histological levels. These aberrations are closely linked to dysfunction of oligodendrocytes and alterations in myelin structure, which may be pivotal factors contributing to the disconnection of brain regions and the resulting characteristic clinical impairments observed in these conditions. Astrocytes, which significantly outnumber neurons in the central nervous system by a five-to-one ratio, play indispensable roles in the development, maintenance, and overall well-being of neurons and oligodendrocytes. Consequently, they emerge as potential key players in the onset and progression of a myriad of neurological and psychiatric disorders. Furthermore, targeting astrocytes represents a promising avenue for therapeutic intervention in such disorders. To gain deeper insights into the functions of astrocytes in the context of myelin-related disorders, it is imperative to employ appropriate in vivo models that faithfully recapitulate specific aspects of complex human diseases in a reliable and reproducible manner. One such model is the cuprizone model, wherein metabolic dysfunction in oligodendrocytes initiates an early response involving microglia and astrocyte activation, culminating in multifocal demyelination. Remarkably, following the cessation of cuprizone intoxication, a spontaneous process of endogenous remyelination occurs. In this review article, we provide a historical overview of studies investigating the responses and putative functions of astrocytes in the cuprizone model. Following that, we list previously published works that illuminate various aspects of the biology and function of astrocytes in this multiple sclerosis model. Some of the studies are discussed in more detail in the context of astrocyte biology and pathology. Our objective is twofold: to provide an invaluable overview of this burgeoning field, and, more importantly, to inspire fellow researchers to embark on experimental investigations to elucidate the multifaceted functions of this pivotal glial cell subpopulation.