Abstract

DiGeorge syndrome chromosomal region 8 (Dgcr8), a candidate gene for 22q11.2 deletion-associated schizophrenia, encodes an essential component for microRNA (miRNA) biosynthesis that plays a pivotal role in hippocampal learning and memory. Adult neurogenesis is known to be important in hippocampus-dependent memory, but the role and molecular mechanisms of adult neurogenesis in schizophrenia remain unclear. Here, we show that Dgcr8 heterozygosity in mice leads to reduced cell proliferation and neurogenesis in adult hippocampus, as well as impaired hippocampus-dependent learning. Several schizophrenia-associated genes were downregulated in the hippocampus of Dgcr8^+/− mice, and one of them, insulin-like growth factor 2 (Igf2), rescued the proliferation of adult neural stem cells both in vitro and in vivo. Furthermore, IGF2 improved the spatial working memory deficits in Dgcr8^+/− mice. These data suggest that defective adult neurogenesis contributes to the cognitive impairment observed in 22q11.2 deletion-associated schizophrenia and could be rectified by IGF2.