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
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
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DOI：
10.1523/jneurosci.2700-12.2013
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发表时间：
2013-05-29
影响因子：
5.3
通讯作者：
Iwamoto, Takashi
中科院分区：
文献类型：
--
作者：
Ouchi, Yasuo;Banno, Yuya;Iwamoto, Takashi
DiGeorge综合征染色体区域8（Dgcr 8）是22q11.2缺失相关精神分裂症的候选基因，编码microRNA（miRNA）生物合成的重要组分，其在海马学习和记忆中起关键作用。成人神经发生在依赖于大脑皮层的记忆中是重要的，但成人神经发生在精神分裂症中的作用和分子机制尚不清楚。在这里，我们表明，Dgcr 8杂合性在小鼠中导致成年海马细胞增殖和神经发生减少，以及受损的海马依赖性学习。在Dgcr 8（+/-）小鼠的海马中，几个精神分裂症相关基因下调，其中之一，胰岛素样生长因子2（Igf 2），在体外和体内都挽救了成体神经干细胞的增殖。此外，IGF 2改善了Dgcr 8（+/-）小鼠的空间工作记忆缺陷。这些数据表明，有缺陷的成人神经发生有助于在22q11.2缺失相关的精神分裂症中观察到的认知障碍，并可以通过IGF 2纠正。
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.