Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis

Abstract

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.

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 Deletion Syndrome

“…Proline, the enzyme produced by PRODH, in interaction with catechol-O-methyl-transferase (COMT) seems to negatively impact brain function in children with 22q11.2DS (103,104). Regarding working memory, the copy number elevations of COMT have been associated with such impairments, not only in 22q11.2DS (105), but also in schizophrenia (106) (but see (107) for different findings). COMT mutations have been argued to result in increased dopamine degradation in the frontal lobes, which could provide a molecular basis for some of the symptomatology associated with both schizophrenia and 22q11.2DS (108,109).…”

Critical reappraisal of mechanistic links of copy number variants to dimensional constructs of neuropsychiatric disorders in mouse models

“…The age of 19 months in mice corresponds to approximately 56 years of age in humans; and 10–14 months of age in mice corresponds to 38–47 years in humans . As working memory deficits due to genetic variants appear in an age‐dependent manner in mice and humans and baseline scores differ at different ages, testing in a much narrower age range from 1 to 3 months might detect a phenotype. Working memory was normal in mouse models of paternal and maternal 15q11–13 duplication, 15q13.3 deletion, and 22q11.2 hemizygous deletion (see Table ).…”

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 deletion syndrome

“…Proline, the enzyme produced by PRODH, in interaction with catechol-O-methyl-transferase (COMT) seems to negatively impact brain function in children with 22q11.2DS 101,102 . Regarding working memory, the copy number elevations of COMT have been associated with such impairments, not only in 22q11.2DS 103 , but also in schizophrenia 104 (but see 105 for different findings). COMT mutations have been argued to result in increased dopamine degradation in the frontal lobes, which could provide a molecular basis for some of the symptomatology associated with both schizophrenia and 22q11.2DS 106,107 .…”