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

Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), characterized by ASD, ADHD, and speech/motor deficits. ANKS1B encodes AIDA-1, a synaptic protein regulating plasticity. Here we identify an unexpected role for oligodendroglial deficits in ANDS pathophysiology. Anks1b-deficient mouse models show impaired oligodendrocyte maturation, myelination, and Rac1 function, recapitulating white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity seen in brain-wide Anks1b haploinsufficiency. Clemastine, an antihistamine that promotes OPC maturation and CNS myelination, rescues social preference deficits in 7-month-old Anks1b-deficient mice. Using FRET-based biosensors, we show loss of AIDA-1 alters Rac1 activation in primary oligodendrocytes, and Rac1 activation (or clemastine) rescues maturation deficits in vitro. These data suggest social behavioral deficits in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.