Tbx1 heterozygosity in the oligodendrocyte lineage has distinct effects on myelinated axons in the fimbria and on behaviors related to neurodevelopmental disorders in mice.

The hemizygous deletion of human chromosome 22q11.2 leads to cognitive and social deficits, as well as psychiatric disorders. Constitutive deletion of Tbx1, a T-box transcription factor gene encoded within this chromosomal region, results in deficits in various cognitive and social behaviors and altered formation of oligodendrocytes, myelin, and myelinated axons in the fimbria of adult mice. Given that Tbx1 is present in neonatal stem cells and oligodendrocytes, the present study was designed to test the hypothesis that Tbx1 heterozygosity in the oligodendrocyte lineage contributes to behavioral phenotypes relevant to neurodevelopmental disorders and ultrastructural changes in myelinated axons in the fimbria. To this end, we conditionally induced Tbx1 heterozygosity in the oligodendrocyte lineage in PdgfrCre;Tbx1+/flox mice. This mouse line showed recombination in brain regions known to express Pdgfr. Male PdgfrCre;Tbx1+/flox mice performed better in spontaneous alternation in a T-maze than wild-type littermates at 1, but not 2 months of age; otherwise, mutant and wild-type littermates were indistinguishable in neonatal ultrasonic vocalization, peripubertal and postpubertal social interaction, novel object approach, anxiety-related behaviors in an elevated plus maze, and motor activity and thigmotaxis in an inescapable open field. The fimbria of male PdgfrCre;Tbx1+/flox mice showed an increase in the number of myelinated axons in a range between [&ge;]300 nm and <800 nm diameter and a decrease in the myelinated axons around 1,200 nm and 1,400 nm; the thickness of myelin was unchanged across all diameters. Our findings show that Tbx1 heterozygosity in oligodendrocyte precursor cells or their progeny selectively improves spontaneous alternation and shifts the proportion of myelinated axons toward small- to medium-sized axons, suggesting that the compositional shift in axons in the fimbria induced by Tbx1 heterozygosity in the oligodendrocyte lineage might underlie improved cognition relevant to neurodevelopmental disorders.