Regeneration, Repair, and Developmental NeuroscienceResearch PaperDisturbances in the positioning, proliferation and apoptosis of neural progenitors contribute to subcortical band heterotopia formation

Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic model of subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental events underlying SBH formation in the neocortex. Our results demonstrate that Pax6+ and Tbr2+ progenitors are mislocalized in tish+/− and tish−/−- neocortex throughout neurogenesis. In addition, mislocalized tish−/− progenitors possess a longer cell cycle than wild type or normally-positioned tish−/− progenitors, owing to a lengthened G2+M+G1 time. This mislocalization is not associated with adherens junction breakdown or loss of radial glial polarity in the ventricular zone (VZ), as assessed by immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ and Par3. However, vimentin immunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish−/− heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish−/− neocortex demonstrate that mislocalized progenitors do not retain contact with the ventricular surface and that ventricular/subventricular zone (SVZ) progenitors produce neurons that migrate into both the heterotopia and cortical plate (CP). Taken together, these findings define a series of developmental errors contributing to SBH formation that differs fundamentally from a primary error in neuronal migration.

Research highlights▶Subcortical band heterotopia (SBH) are neocortical malformations associated with epilepsy. ▶SBH formation is generally thought to result from errors in neuronal migration. ▶We examined SBH formation using a novel animal model, the tish rat. ▶Errors leading to tish SBH formation differ from errors in neuron migration.