Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via interleukin-1

Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, suggesting viruses impact these processes. Here, using an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in gene expression that limit adult neurogenesis, including interleukin (IL)-1. WNND-recovered animals exhibit decreased neuroblasts and increased astrogenesis, without recovery of hippocampal neurogenesis at thirty days. Analysis of cytokine production in ex vivo isolated microglia and astrocytes revealed the latter to be the predominant source of IL-1. IL-1R1-deficient, WNND-recovered mice exhibit normal neurogenesis, recovery of presynaptic termini, and resistance to spatial learning defects, the latter of which likewise occurred after treatment with IL-1R1 antagonist. Thus, preferential generation of proinflammatory astrocytes impairs neuronal progenitor cell homeostasis via expression of IL-1, which may underlie long-term cognitive consequences of WNND, but provides a therapeutic target.