Usunięcie genu mikrocefałii Cit-k w oligodendrocytach zakłóca łączność kory mózgowej i funkcje poznawcze
Oligodendroglial deletion of the microcephaly gene Cit-k disrupts cortical connectivity and cognitive function
W skrócie
[Preprint - wstępne wyniki] Badacze wykazali, że utrata białka CIT-K w komórkach myelinowych (oligodendrocytach) powoduje niedostateczną izolację włókien nerwowych i prowadzi do trwałych zaburzeń pamięci, motoryki i zwiększonej podatności na napady padaczki. Wyniki badań na myszach wskazują, że uszkodzenie komórek odpowiedzialnych za tworzenie osłonki nerwowej może być głównym czynnikiem choroby mikrocefałii typu 17, a nie tylko wtórną konsekwencją wad neurologicznych. Odkrycie to sugeruje, że zaburzenia mieliny odgrywają ważną rolę w rozwojowych zaburzeniach mózgu i mogą być ważnym celem dla przyszłych terapii.
Oryginalny abstract (angielski)
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 CIT 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. Here, we investigated the specific role of oligodendroglial Cit-k loss using Sox10Cre;Cit-kfl/fl 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. 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.