Abstract Cognitive deficits are major disabling impairments associated with neurodevelopmental disorders. Currently available drugs have poor efficacy due to a limited understanding of the genetic and cellular mechanisms underlying these deficits. Our project addresses this unmet need by exploring the mechanistic underpinnings of cognitive deficits. Copy number variants (CNVs), such as a 1.5 Mb hemizygous deletion of 22q11.2, and variants of single genes, such as heterozygous variants of Tbx1, a 22q11.2 gene, have been associated with a high risk of cognitive deficits in humans and serve as promising mechanistic entry points. As many social, memory, and cognitive deficits in individuals with these genetic variants manifest during childhood (i.e., a postnatal period after birth and before full adulthood), our previous work focused on post-embryonic cellular events. We showed that the heterozygosity of Tbx1 in early postnatal neural stem cells contribute to deficits in social interactions and that altered postnatal myelination in the fimbria may represent a potential cellular substrate for impaired cognitive speed. This proposed project will test the overarching hypothesis that alterations in postnatal myelination due to dose alterations of genes implicated in neurodevelopmental disorders negatively impact cognitive speed. To allow for the disambiguation of the relative roles of postnatal oligodendrogenesis and postnatal neurogenesis in cognitive speed, we developed two conditional Tbx1 heterozygous mouse models: Ng2CreER;Tbx1flox/+ and nesCreERT2;Tbx1flox/+ mice. To evaluate the relative roles played by Tbx1 and 22q11.2 CNV in cognitive speed, we will include a mouse model of 22q11.2 hemizygous deletion. Aim 1 will evaluate the impacts on cognitive speed of conditional heterozygous Tbx1 deletion from postnatal stem/progenitor cells of oligodendrocyte or neuronal lineage in mice and determine the relative contributions to cognitive speed of Tbx1 deficiency compared with global 22q11.2 hemizygosity. We will use rodent tasks for spatial memory, cognitive flexibility, and working memory, as the speed of these cognitive dimensions are negatively impacted from childhood among carriers of 22q11.2 hemizygosity. Aim 2 will identify regions with altered white matter integrity, assess axonal myelination in affected brain regions, and evaluate the conductance speed of myelin-deficient pathways using diffusion tensor imaging (DTI)-MRI, electron microscopy, and electrophysiological recordings, respectively, in the three mouse models. Aim 3 will evaluate the in vivo functional roles of TBX1’s target genes in the cognitive functions in mutant mice and establish the precise cellular processes associated with postnatal oligodendrogenesis and myelin production in vivo and in vitro. The current proposal will reveal novel postnatal cellular mechanisms associated with a distinct dimension of cognitive function, improving our understanding of the cellular mechanisms con...