Abstract
<jats:title>Abstract</jats:title> <jats:p> Neurodevelopmental disorders (NDDs) are increasingly recognized as disorders of brain connectivity and circuit dysfunction. Growing evidence suggests that glial cell and myelin abnormalities may actively contribute to these alterations. Yet, they have been often considered secondary consequences of impaired neuronal development rather than primary drivers of circuit dysfunction. Primary autosomal recessive microcephaly type 17 (MCPH17) is a severe NDD caused by mutations in the <jats:italic>CIT</jats:italic> gene, encoding Citron kinase (CIT-K). The disease is associated with cognitive and motor deficits, epilepsy susceptibility, and marked hypomyelination in both patients and mouse models, suggesting a contribution of oligodendroglial dysfunction to disease pathophysiology. </jats:p> <jats:p> Here, we investigated the specific role of oligodendroglial Cit-k loss using Sox10 <jats:sup>Cre</jats:sup> ;Cit-k <jats:sup>fl/fl</jats:sup> mice, in which Cit-k is selectively deleted in oligodendrocyte-lineage cells. Mutant mice displayed impaired forebrain myelination at juvenile stages and persistent cortical hypomyelination in adulthood. Despite preserved gross motor function, adult mutants showed deficits in fine motor control, working and recognition memory, and auditory fear memory. These impairments were associated with altered cortico-cortical and cortico-hippocampal functional connectivity. Moreover, consistent with the clinical MCPH17 phenotype, mutant mice exhibited increased susceptibility to kainate-induced seizures. </jats:p> <jats:p>Together, our findings show that oligodendroglial Cit-k loss and the resulting hypomyelination are sufficient to produce long-lasting neurological and behavioral impairments independently of primary neuronal defects. These results identify oligodendrocytes as active contributors to MCPH17 and support a broader role for myelin abnormalities in NDDs.</jats:p> <jats:sec> <jats:title>Highlights</jats:title> <jats:list list-type="bullet"> <jats:list-item> <jats:p>Cit-k deletion in oligodendroglia disrupts forebrain myelination</jats:p> </jats:list-item> <jats:list-item> <jats:p>Cortical hypomyelination persists in adult mutant mice</jats:p> </jats:list-item> <jats:list-item> <jats:p>Mutant mice show deficits in motor control and memory</jats:p> </jats:list-item> <jats:list-item> <jats:p>Cortico-cortical and cortico-hippocampal connectivity are altered</jats:p> </jats:list-item> <jats:list-item> <jats:p>ligodendrocytes contribute to microcephaly-associated dysfunctions</jats:p> </jats:list-item> </jats:list> </jats:sec>