title: Reduced adult hippocampal neurogenesis and working memory deficits in the Dgcr8-deficient mouse model of 22q11.2 deletion-associated schizophrenia can be rescued by IGF2.
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.
authors.affiliation: The Center for Education in Laboratory Animal Research, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, 487-8501, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ouchi
authors.forename: Yuya
authors.initials: Y
authors.lastname: Banno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Shouta
authors.initials: S
authors.lastname: Ando
authors.forename: Hitoki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Adachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwamoto
mesh_terms: D000818:Animals; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D005260:Female; D017353:Gene Deletion; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology*; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009043:Motor Activity / Q000502:physiology; D009425:Nesting Behavior / Q000502:physiology; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D013550:Swimming / Q000523:psychology
chemical_list: D000963:Antimetabolites; C474044:Dgcr8 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D012313:RNA; D007335:Insulin-Like Growth Factor II; D001973:Bromodeoxyuridine