Oligodendroglial hypothesis of autism: the primary role of master regulator gene Baf155 [RNA-Seq]

Autism spectrum disorders (ASD) are polyetiological neurodevelopmental disorders associated with both genetic and non-genetic risk factors with complex and heterogeneous clinical manifestations. A single susceptibility gene usually fails in triggering an intricate array of autistic symptoms, suggesting a primary mechanism may be required to integrate multiple susceptibility genes in casing the disease. Recent evidence highlights the role of myeline disruption in pathogenesis of ASD. However, neither the mechanisms of impaired myelination nor its contribution to ASD symptomatology are fully characterized. We demonstrate the loss of Baf155, a newly recognized autistic susceptibility gene that encodes a core member of the chromatin remodeling complex, affects oligodendroglial differentiation and myelination. BAF155 targets multiple synapse-related genes in oligodendrocyte precursor cells (OPCs), these genes being responsible for regulating the synaptic communication between OPCs and neurons. Heterogeneous target genes affected by BAF155 deficiency in OPCs across various brain regions leads to significant impairments in myelination which may contribute to the diverse manifestations observed ASD patients. Taken together, our findings reveal a primary mechanism that orchestrates multiple ASD susceptibility genes in instigating the disease. Overall design: To investigate whether BAF155 modulates the responses of OPCs to neuronal inputs in distinct brain regions, we assessed the differentially expressed genes in acutely isolated OPCs from mPFC and hippocampus of Baf155 knockout mice and their non-Cre littermates by RNA-seq . In line with that, we analyzed the variability of OPCs from mPFC and hippocampus response to different neurotransmitters(Glutamate/GABA) by RNA-seq.