Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Abstract

Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.

Neocortical and cerebellar malformations affect flurothyl-induced seizures in female C57BL/6J mice

“…We have previously described the prevalence and cytoarchitecture of neocortical and cerebellar heterotopia in C57BL/6J mice (Ramos et al, 2008;Toia et al, 2017). Consistent with our previous work, we found that a large proportion of mice had cerebellar and/or neocortical heterotopia.…”

“…Brightfield microscopy at varying magnifications (4, 20, and/or 40X) was used to screen sections for cerebellar and neocortical malformations. Digital photomicroscopy was used to document malformations according to methods previously used to identify both cerebellar (Van Dine et al, 2013a,b, 2015Ramos et al, 2015) and neocortical malformations (Ramos et al, 2008;Toia et al, 2017). Statistical analysis and creation of graphs were performed via GraphPad Prism version 9.4.0 with significance levels set at a p-value of <0.05.…”