Chd8 haploinsufficient mice display various ASD-like phenotypes that parallel the clinical signature of individuals with de-novo CHD8 mutations (10, 11, 13, 24). Consistent with retrospective patient head circumference data, mouse models for CHD8 haploinsufficiency suggest a postnatal onset of abnormal head growth (10, 11). In this study, we queried the neuroanatomy of Chd8+/− and litter-matched E12.5 control mice using light-sheet microscopy to determine whether morphological anomalies in brain and cortical cell shape could preindicate ASD-associated macrocephaly.
The results from a number of longitudinal studies of postnatal volumetric brain changes have implicated neuroanatomical abnormalities in cortical thickness, ventricular morphology, cortical overgrowth, and increased cortical surface area in the complex trajectory of brain development in individuals with ASD (6, 25–30). Accordingly, our work characterized cortical thickness along with volumetric features to confirm whether analogous morphological alterations were observable in haploinsufficient mouse brains. We note that in this particular instance, no significant discrepancies in cortical thickness, ventricular and cortical volumes, or surface areas between groups could be determined. In line with the heterogeneous nature of ASD, it is reasonable to assume that other brain regions may be affected instead. Notably, we provide experimental evidence of dissimilarities in ventricular sphericity and intraocular distance that mirror known phenotypes in haploinsufficient adult mice (Fig. 2) (10).
Similarly, a number of aberrations at the cellular scale have been reported in ASD during the establishment of cortical microarchitecture (26). Consequently, we sought to ascertain differences in the cortical organization between groups as defined by patterns of cell geometric features measured on the apical surface (Fig. 3). Having quantified epithelial morphology according to the cell area, aspect ratio, neighbour topology, and adherence to empirical laws such as Lewis’ and Aboav-Weaire’s (Fig. 3), our data showed no departure in the cortical organization between haploinsufficient brains and controls, suggesting similar mechanical behaviour (20, 22).
In this work, we present a multi-scale assessment of the embryonic neuroanatomical implications of Chd8 haploinsufficiency in mice. We propose that an increased understanding of the identified organ-level differences may shed light on the etiology of hypertrophic brain growth. What is more, our approach opens exciting avenues to investigate the presence of cellular alterations in other implicated brain regions and phenotypic differences across diverse Chd8 haploinsufficient mouse models, all of which have a wide range of dosage-specific, dimorphic, and behavioural signatures (24, 31).