Targeting oligodendroglial cell dysfunctions to treat cognitive defects and epilepsy in primary autosomal recessive microcephaly-17 (MCPH17) models

Primary autosomal recessive microcephaly-17 (MCPH17) is a genetic form of microcephaly caused by mutations in the CIT gene. Depending on the mutation, MCPH17 patients show a variable degree of neuroanatomical alterations and functional defects. Long-survivor patients display seizures and intellectual disability. MCPH17 mouse models are available and recapitulate the main features of the pathology. So far, research on MCPH17 has been exclusively concentrated to the neurogenesis/neuronal defects associated with CIT mutations. Yet, in recent studies in MCPH17 mouse models and patients, we found significant alterations in non-neuronal cells, i.e. oligodendrocytes (OLs), and demonstrated that OLs are affected independently of the neurogenesis/neuronal defects and may contribute per se to the cognitive impairment of MCPH17 mice. We also found that, despite not correcting microcephaly, a postnatal anti-oxidant treatment partly rescued OL dysfunction, and significantly reduced the epileptic manifestations and motor defects in MCPH17 mouse models. Based on these findings, here we propose a combination of different experimental approaches and pharmacological manipulations to target OL dysfunctions, in order to sustain neuronal/circuitries maturation and function in MCPH17 models and possibly offer a novel therapeutic option that could improve MCPH17 patients’ quality of life.