Decades of research have documented abnormal white matter integrity1–4 and reduced axonal conduction velocities5, 6 in people with idiopathic and syndromic autism spectrum disorder (ASD). Despite this extensive evidence, white matter issues have typically been seen as secondary to neuronal deficits.
Recent studies are challenging this view, suggesting that myelination deficits are primary to ASD etiology. Oligodendrocyte-specific haploinsufficiency of Chd8, a gene robustly linked to ASD etiology, leads to impaired social behavior and anxiety in mice7. Similarly, mice with oligodendrocyte-specific haploinsufficiency of the Anks1b gene display the ASD-like behavioral correlates of ANKS1B neurodevelopmental syndrome (ANDS)8. Moreover, treatment with clemastine, a compound known to enhance myelination, improves social deficits in both the ANDS mouse model8, and a mouse model of the ASD Pitt-Hopkins syndrome9.
Building on this research, Bryen Jordan and colleagues predict that dysfunctions of oligodendrocytes and myelination are central to the pathophysiology of ASD. Preliminary findings show that many ASD-genes linked to synaptic function are expressed in oligodendrocytes, their findings suggest that ASD may be rooted in problems with noncanonical synapses formed between neurons and oligodendrocytes.
This proposal will determine whether behavioral correlates of ASD associated with different well-studied ASD mouse models (including SHANK3, SYNGAP1 and NLGN1) originate from oligodendrocyte dysfunctions. Furthermore, they plan to assess whether ameliorating myelination pharmacologically using clemastine or sobetirome can rescue these deficits. Findings from these studies are expected to challenge existing perceptions of synaptopathies in autism and catalyze a paradigm shift in understanding ASD etiology.