Fetal Cortical Layers and Midline Histological Alterations in the BTBR Mouse Model of Neurodevelopmental Disorders

The BTBR T+ Itpr3tf/J (BTBR) strain is a widely used model of neurodevelopmental disorders, characterized by an altered neuroanatomy, including a full-penetrant agenesis of the corpus callosum. While the adult BTBR brain has been studied thoroughly, less is known about how its brain develops prenatally and about when neurodevelopmental trajectories begin to differ from neurotypical strains. Here, we conducted a comparative histological analysis of fetal brain development across multiple developmental stages in BTBR and C57BL/6J (B6) mice, focusing on neocortical and midline development. BTBR mice showed lower fetal weight but comparable somite counts (assessed at 12.5 days post coitum, dpc) compared to B6 controls, indicating similar developmental timing. Neocortical layering showed a reduced ventricular zone fraction in BTBR fetuses at 15.5 dpc, without a change in overall cortical thickness. Concurrently, midline cell populations immunoreactive for the glutamate aspartate transporter (GLAST) failed to undergo remodeling in subsequent stages, resulting in the failure to form a GLAST+ indusium griseum and the lack of callosal projections crossing the midline at 17.5 dpc, which instead develop normally in B6 fetuses. These findings offer structural correlates for the early neuropathology of the BTBR brain.