Abstract: Multiple sclerosis (MS) is characterized as an inflammatory demyelinating disease that affects the central nervous system (CNS), leading to sensory, motor and cognitive impairments. Ultimately, axonal denudation culminates in axonal lesions and neurodegeneration. Inflammatory demyelinating lesions in MS are associated with infiltration of immune cells combined with activation of the resident CNS inflammatory cells, astro- and microglia. Recently, synaptopathy has been associated with MS pathophysiology, though, intriguingly, it can occur independently of demyelination (Jürgens et al., 2016). Although inflammation also seems to corroborate with synaptic abnormalities, associated or not with demyelinating lesions, the underlying mechanisms are not fully understood (Mandolesi et al., 2015). In the last decades, the myelin inhibitory protein neurite outgrowth inhibitor-A (Nogo-A) has emerged as a potential mediator of axonal and synaptic dysfunctions in MS and a promising target to be neutralized  (Ineichen et al., 2017). Based on our recent findings demonstrating that Nogo-A signaling regulates astrocyte-driven synaptogenesis (Espírito-Santo et al., 2021),  and considering the critical role of astrocytes in regulating synaptic plasticity and function (Allen and Eroglu, 2017), we propose that modulation of Nogo-A pathway in these cells is a new mechanism driving circuitry alterations of MS.