ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function

Abstract Our understanding of oligodendrocytes in brain function and disease is changing rapidly. We recently reported that heterozygous deletions in the ANKS1B gene lead to ANKS1B syndrome, a neurodevelopmental disorder presenting with autism spectrum disorder (ASD), attention deficit hyperactivity disorder, and speech and motor deficits. ANKS1B encodes for AIDA-1, a brain-specific protein that is highly enriched at neuronal synapses where it regulates NMDA receptor function and synaptic plasticity. Deficits in neuronal transmission are therefore implicated in the etiology of ANKS1B syndrome. Here we reveal an unexpected role for ANKS1B in oligodendrocyte function, and a potential role for oligodendrocytes in disease pathophysiology. Mouse models of ANKS1B syndrome display structural and white matter abnormalities in the corpus callosum that are reminiscent of clinical findings in patients. Immunochemical and histological analyses show that reduced oligodendrocyte abundance, maturation, and myelination likely underlie callosal structural abnormalities. We report that AIDA-1 protein is highly expressed in oligodendrocytes and oligodendrocyte precursor cells (OPCs) in addition to neurons. Surprisingly, selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations that highly express AIDA-1, lead to deficits in social preference and sensory reactivity, behavioral correlates of ASD previously observed in a CNS-wide Anks1b haploinsufficiency model. Notably, we find that clemastine fumarate, a compound shown to increase OPC maturation and CNS myelination, rescues deficits in social preference in these mice at 7-months of age. Our work shows that deficits in social behaviors present in ANKS1B syndrome may originate from oligodendrocyte dysfunctions and illustrates an important role for oligodendrocytes in neurodevelopmental disorders.