<i>Chd8</i> haploinsufficiency leads to molecular layer heterotopias and age-dependent cortical expansion

Mutations in the chromatin remodeler <i>CHD8</i> are associated with autism and macrocephaly. While mouse models of <i>Chd8</i> haploinsufficiency recapitulate brain overgrowth, the specific cellular mechanisms and developmental timing that lead to these anatomical abnormalities remain poorly understood. Here, we conducted 3D imaging of <i>Chd8</i> ^V986*/+ mouse brains using magnetic resonance imaging followed by tissue clearing and cellular resolution light-sheet microscopy across embryonic and postnatal developmental stages. We found that brain overgrowth occurs postnatally, driven by an expansion of oligodendrocytes and microglia. Unexpectedly, we identified prevalent molecular layer heterotopias within the frontal cortex of <i>Chd8</i> ^V986*/+ mice appearing during embryonic development and persisting throughout life. Molecular layer heterotopias were previously identified in post-mortem brains from individuals with autism and other neurodevelopmental disorders, suggesting functional significance in human patients.