Fig 2: Schematic model for effects of SEMA4D on astrogliosis. In keeping with published data of others regarding changes in reactive astrocyte function, it is suggested that SEMA4D is upregulated in stressed neurons and binds to PLXN-B1/B2 receptors to trigger reactive astrocytes, characterized by morphologic reorganization of the cytoskeleton and retraction of dendritic processes, downregulation of glucose and lactate transporters (GLT1 and MCT), downregulation of glutamate receptor (EAAT2), and reduction in glutamine synthetase (GS), key functional transporters and enzymes in astrocytes. SEMA4D-induced reactive changes indicated by red arrows. Dysfunctional transport and conversion of metabolic and neurotransmitter substrates may reduce astrocytic neuroprotection mechanisms and impair recycling glutamate to glutamine in astrocytes and glutamine to glutamate and GABA in neurons. Image created with BioRender.com; adapted from Bélanger, Allaman, Magistretti. Cell Metab. 2011