CORTICAL HYPOMYELINATION IS ASSOCIATED WITH COGNITIVE IMPAIRMENT IN A MOUSE MODEL OF OLIGODENDROGLIA-SPECIFIC CITRON KINASE ABLATION

Citron Kinase (Cit-k) is a serine-threonine kinase involved in DNA repair and cytoskeletal dynamics, whose loss-of-function results in microcephaly and severe CNS hypomyelination in both humans and mice. In the conditional oligodendrocyte-specific Cit-k mouse mutant (Sox10Cre::Cit-k fl/fl mice), Cit-k loss cell-autonomously induces forebrain oligodendrocyte progenitor cells to either undergo cell death or enter a senescent state, leading to diffuse impairment of myelin deposition at juvenile stages. This myelin defect is only partially compensated in adult mice, where a severe hypomyelination persists selectively in the cerebral cortex – but not in other brain areas. Given the growing evidence supporting the link between myelination and cognitive function, we assessed whether this region-specific hypomyelination was associated with functional alterations from postnatal development to adulthood. While gross motor and sensory aspects appeared unaltered throughout the mutant’s lifespan, analysis of spontaneous ultrasonic vocalizations in the Sox10Cre::Cit-k fl/fl pups highlighted dynamic impairments during the first postnatal weeks, suggesting alterations in early cognitive development. Furthermore, adult mutants displayed impaired working, short term and associative fear memories (as assessed by Y maze, Novel Object Recognition and Fear conditioning tests) despite the partial recovery of myelination. Alterations in cortico-cortical and cortico-hippocampal functional connectivity accompany the observed cognitive impairment. Overall, our data indicates that the regionalized hypomyelination resulting from the oligodendroglia-specific deletion of Cit-k is associated with specific cognitive deficiencies that persist from postnatal development to adulthood. These results support the notion that disrupted myelination may compromise network activity and contribute to long-term dysfunction.