Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.

中文翻译：

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22q11.2基因的拷贝数升高阻止了工作记忆能力和成人海马神经发生的发育成熟。

工作记忆能力是执行功能的重要组成部分，从童年到成年期都在发展。在患有自闭症谱系障碍（ASD），精神分裂症和智力障碍（ID）的个体中可以看到这种发育过程的异常，这暗示了这种非典型过程与发育性神经精神疾病的轨迹有关。但是，尚不了解此过程的细胞和神经元底物。22q11.2的拷贝数变异的复制和重复与人类ASD和ID的认知缺陷一致且牢固相关，小的22q11.2片段的过表达概括了小鼠发育性神经精神疾病的维度方面。我们利用这两条证据来探究工作记忆的这种非典型发展的细胞基质。使用区域和细胞类型选择性基因表达方法，我们证明了成年神经干中儿茶酚-O-甲基转移酶（COMT）或Tbx1的拷贝数升高，这两个基因编码在两个小的22q11.2节中海马中的/祖细胞阻止了小鼠工作记忆能力的发育成熟。此外，COMT或Tbx1的拷贝数升高在体外以细胞自主方式减少了成年神经干/祖细胞的增殖，并在体内使它们的后代迁移到海马颗粒层中。我们的数据为新颖的假设提供了证据，这些假设是这些22q11的拷贝数升高。