The upregulation of SEMA4D/Plexin B1 signalling and the importance of neuroglia interactions driving the pathology of Rett syndrome provide a mechanistic rationale for the amelioration of Rett syndrome-specific symptoms and the improvement of behavioural functions in anti-SEMA4D antibody-treated Mecp2T158A/y mice. The gene discussed is SEMA4D; the disease is atypical Rett syndrome.