Oligodendroglial deletion of the microcephaly gene Cit-k disrupts cortical connectivity and cognitive function

Neurodevelopmental disorders (NDDs) are increasingly viewed as disorders of brain connectivity, but glial and myelin abnormalities are often considered secondary to neuronal defects. MCPH17 is a severe NDD caused by mutations in the CIT gene, encoding Citron kinase (CIT-K), and is associated with cognitive and motor deficits, epilepsy susceptibility, and marked hypomyelination in patients and mouse models. To test whether oligodendroglial dysfunction directly contributes to disease, researchers generated Sox10Cre;Cit-k fl/fl mice with Cit-k selectively deleted in oligodendrocyte-lineage cells. These mutants showed impaired forebrain myelination at juvenile stages and persistent cortical hypomyelination in adulthood. Although gross motor function was preserved, adult mutants exhibited deficits in fine motor control, working and recognition memory, and auditory fear memory, alongside altered cortico-cortical and cortico-hippocampal functional connectivity. Mutants also showed increased susceptibility to kainate-induced seizures, consistent with the clinical MCPH17 phenotype. These findings demonstrate that oligodendroglial Cit-k loss and resulting hypomyelination are sufficient to produce long-lasting neurological and behavioral impairments independently of primary neuronal defects, identifying oligodendrocytes as active contributors to MCPH17 and supporting a broader role for myelin abnormalities in NDDs.