Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice

• Published in: Molecular psychiatry Vol. 27; no. 2; pp. 929 - 938
• Main Authors: Hiramoto, Takeshi, Sumiyoshi, Akira, Yamauchi, Takahira, Tanigaki, Kenji, Shi, Qian, Kang, Gina, Ryoke, Rie, Nonaka, Hiroi, Enomoto, Shingo, Izumi, Takeshi, Bhat, Manzoor A., Kawashima, Ryuta, Hiroi, Noboru
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2022; Nature Publishing Group
• Subjects: 101/28; 13; 59/57; 631/378; 64/60; 692/699/476/1373; Accuracy; Animal cognition; Animals; Axons; Behavioral Sciences; Biological Psychology; Brain; Chromosome 22; Chromosome deletion; Cognition; Cognitive ability; Cognitive development; Copy number; DNA Copy Number Variations - genetics; Fornix; Gene deletion; Genes; Glial stem cells; Health sciences; Heterozygote; Magnetic resonance imaging; Medicine; Medicine & Public Health; Memory; Mental disorders; Mice; mRNA; Myelination; Neuroimaging; Neurosciences; Oligodendrocytes; Oligodendroglia; Pharmacotherapy; Progenitor cells; Proteins; Psychiatry; Schizophrenia; Spatial memory; Stem cells; Subventricular zone; T-Box Domain Proteins - genetics; Tbx1 protein; Variance analysis
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-021-01318-4

Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1 , one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in myelin. The fimbria of Tbx1 heterozygous mice showed reduced mRNA levels of Ng2 , a gene required to produce oligodendrocyte precursor cells. Moreover, postnatal progenitor cells derived from the subventricular zone, a source of oligodendrocytes in the fimbria, produced fewer oligodendrocytes in vitro. Behavioral analyses of these mice showed selectively slower acquisition of spatial memory and cognitive flexibility with no effects on their accuracy or sensory or motor capacities. Our findings provide a genetic and cellular basis for the compromised cognitive speed in patients with 22q11.2 hemizygous deletion.