N-acetyl cysteine rescues cortical glial cell populations and results in functional improvements in a mouse model of primary autosomal recessive microcephaly 17 (MCPH17)

Primary autosomal recessive microcephaly 17 (MCPH17) is a rare neurodevelopmental disorder caused by mutations in the CIT gene, which encodes for the Citron Kinase (CIT-K), a kinase involved in DNA repair and cytoskeletal dynamics. Patients show reduced brain volume, intellectual disability, motor deficits, epilepsy, and early mortality. Cit-k KO mice recapitulate MCPH17 phenotype. In the Cit-k KO mouse brain, DNA damage and reactive oxygen species (ROS) accumulation is accompanied by neural progenitor apoptosis and glial cell alterations, including oligodendroglia and astroglia reduction, hypomyelination, and increased numbers of microglia presenting dysmorphic features and engulfed synaptic material. To identify pharmacological treatments that can reduce cellular damage accumulation and improve the functional phenotype of Cit-k KO mice, we chronically treated Cit-k KO mice during the first 2 postnatal weeks with an FDA-/EMA-approved antioxidant drug N-acetylcysteine (NAC), which can pass the blood-brain-barrier. NAC treatment reduced brain ROS levels and slightly increased Cit-k KO mouse life span. Treated mice showed motor improvement and reduction of epileptic myoclonus. Deposition of perineuronal nets around cortical parvalbumin-positive interneurons was significantly rescued by NAC treatment, suggesting a positive effect on the maturation/function of inhibitory neurons. Although NAC did not rescue Cit-k KO mouse hypomyelination, cortical oligodendrocytes and astrocytes significantly increased in numbers, while microglia density and dysmorphic features decreased. Our data suggest, in the Cit-k KO mouse cortex, NAC-induced functional improvements may be at least in part mediated by the correction of Cit-k KO glial cell dysfunctions. Ongoing analyses will unveil the functional bases of NAC effects.