Oligodendrocyte precursor cells, which persist in the adult central nervous system, are the main source of central nervous system remyelinating cells. In multiple sclerosis, some demyelinated plaques exhibit an oligodendroglial depopulation, raising the hypothesis of impaired oligodendrocyte precursor cell recruitment. Developmental studies identified semaphorins 3A and 3F as repulsive and attractive guidance cues for oligodendrocyte precursor cells, respectively. We previously reported their increased expression in experimental demyelination and in multiple sclerosis. Here, we show that adult oligodendrocyte precursor cells, like their embryonic counterparts, express class 3 semaphorin receptors, neuropilins and plexins and that neuropilin expression increases after demyelination. Using gain and loss of function experiments in an adult murine demyelination model, we demonstrate that semaphorin 3A impairs oligodendrocyte precursor cell recruitment to the demyelinated area. In contrast, semaphorin 3F overexpression accelerates not only oligodendrocyte precursor cell recruitment, but also remyelination rate. These data open new avenues to understand remyelination failure and promote repair in multiple sclerosis.

Neural stem cells (NSCs) persist in defined brain niches, including the subventricular zone (SVZ), throughout adulthood and generate new neurons destined to support specific neurological functions. Whether brain diseases such as multiple sclerosis (MS) are associated with changes in adult NSCs and whether this might contribute to the development and/or persistence of neurological deficits remains poorly investigated. We examined SVZ function in mice in which we targeted an MS-like pathology to the forebrain. In these mice, which we refer to herein as targeted EAE (tEAE) mice, there was a reduction in the number of neuroblasts compared with control mice. Altered expression of the transcription factors Olig2 and Dlx2 in the tEAE SVZ niche was associated with amplification of pro-oligodendrogenic transit-amplifying cells and decreased neuroblast generation, which resulted in persistent reduction in olfactory bulb neurogenesis. Altered SVZ neurogenesis led to impaired long-term olfactory memory, mimicking the olfactory dysfunction observed in MS patients. Importantly, we also found that neurogenesis was reduced in the SVZ of MS patients compared with controls. Thus, our findings suggest that neuroinflammation induces functional alteration of adult NSCs that may contribute to olfactory dysfunction in MS patients.

Promoting remyelination to prevent/reduce neurodegeneration in patients with multiple sclerosis (MS) is a major therapeutic goal. The longstanding view that the block of oligodendrocyte progenitor cell (OPC) differentiation in MS lesions is the leading cause of remyelination failure has inspired the scientific community to focus primarily on OPC differentiation-promoting compounds as pro-remyelinating agents. Yet, these strategies have been challenged by findings that active MS lesions contain surviving oligodendrocytes that may contribute to remyelination, while many chronic lesions contain low numbers of oligodendroglial cells. In addition, clinical trials using differentiation-stimulating drugs have shown limited efficacy. Thus, a strategic shift in the design of potential remyelination-promoting therapies may be required to achieve significant clinical benefits, which calls for a careful reconsideration of the mechanisms underlying remyelination failure in MS. Here, we argue that both the rate and the efficacy of OPC recruitment are fundamental determinants of remyelination, and that stimulating this process in MS may be crucial to achieve myelin regeneration. We first review different types of MS lesions in early and chronic MS, with a particular focus on OPCs and surviving oligodendrocytes. Based on the neuropathological findings and results obtained using models of demyelination, we make the case that OPC differentiation block in chronic MS is likely the consequence of defective OPC recruitment during earlier phases of the disease, because (i) if the recruitment is too slow, OPCs reach the axons after what we define as ‘remyelination-permissive window’, and thus remain undifferentiated; and (ii) if the recruitment is inefficient, OPC density in the lesions remains below the threshold required for differentiation. Importantly, we highlight that OPC proliferation in MS lesions is scarce, which strongly suggests that repeated episodes of demyelination/remyelination (OPC differentiation) will deplete the lesional OPC pool unless perilesional OPCs are recruited. We also point out that surviving mature oligodendrocytes in a subtype of early MS lesions may actually prevent the recruitment of OPCs. Because it has been suggested that OPC-mediated remyelination may be more efficient than that by surviving oligodendrocytes, we suggest that stimulating OPC recruitment during active disease should benefit remyelination in multiple types of lesions, including those with spared oligodendrocytes. Finally, we review molecular determinants of OPC recruitment and suggest a potential therapeutically-relevant strategy to increase this process in patients with MS.

The discovery of cannabinoid receptors as the primary molecular targets of psychotropic cannabinoid Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC) in late 1980s paved the way for investigations on the effects of cannabis‐based therapeutics in brain pathology. Ever since, a wealth of results obtained from studies on human tissue samples and animal models have highlighted a promising therapeutic potential of cannabinoids and endocannabinoids in a variety of neurological disorders. However, clinical success has been limited and major questions concerning endocannabinoid signaling need to be satisfactorily addressed, particularly with regard to their role as modulators of glial cells in neurodegenerative diseases. Indeed, recent studies have brought into the limelight diverse, often unexpected functions of astrocytes, oligodendrocytes, and microglia in brain injury and disease, thus providing scientific basis for targeting glial cells to treat brain disorders. This Review summarizes the current knowledge on the molecular and cellular hallmarks of endocannabinoid signaling in glial cells and its clinical relevance in neurodegenerative and chronic inflammatory disorders.

Central nervous system (CNS) myelin has a crucial role in accelerating the propagation of action potentials and providing trophic support to the axons. Defective myelination and lack of myelin regeneration following demyelination can both lead to axonal pathology and neurodegeneration. Energy deficit has been evoked as an important contributor to various CNS disorders, including multiple sclerosis (MS). Thus, dysregulation of energy homeostasis in oligodendroglia may be an important contributor to myelin dysfunction and lack of repair observed in the disease. This article will focus on energy metabolism pathways in oligodendroglial cells and highlight differences dependent on the maturation stage of the cell. In addition, it will emphasize that the use of alternative energy sources by oligodendroglia may be required to save glucose for functions that cannot be fulfilled by other metabolites, thus ensuring sufficient energy input for both myelin synthesis and trophic support to the axons. Finally, it will point out that neuropathological findings in a subtype of MS lesions likely reflect defective oligodendroglial energy homeostasis in the disease.