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IntroductionAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.MethodsWe used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.ResultsThrough MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.ConclusionThese findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.

Proper development and function of the central nervous system require precise regulation of gene expression. MicroRNAs (miRNAs), a group of small non-coding RNAs that can negatively regulate gene expression at the post-transcriptional level, are critical regulators of neuronal development, and dysregulation of microRNAs has been implicated in various neurological disorders. Changes in microRNA expression and repertoire are related to the emergence of social and behavioral variations in closely related primates, including humans, during evolution. MicroRNA-514a (miR-514a) is an X-linked miRNA that is conserved in species with higher social and cognitive functions, and frequent tandem duplications of miR-514a have been found in primate genomes. Here, we demonstrate that miR-514a plays a crucial role in neuronal development in neurons derived from human induced pluripotent stem cells (iPSCs). Overexpression of miR-514a increased dendritic length, soma size, and activity levels of mammalian target of rapamycin (mTOR) signaling in induced pluripotent stem cell-derived neurons, whereas blocking of endogenous miR-514a inhibited neuronal development. Furthermore, we performed a functional analysis of the miR-514a variation found during primate evolution, to investigate the impact of miR-514a sequence variation and associated changes in expression on brain development during evolution. We found that mutation in miR-514a significantly reduced the expression of the mature form and abolished the effects observed when native miR-514a was expressed. Our findings provide new insights into the functional role of miR-514a in the regulation of neuronal development and evolution of primate brain development.

Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder characterized by various neurological symptoms. Almost all RTT cases are caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, and several mouse models have been established to understand the disease. However, the neuroanatomical abnormalities in each brain region of RTT mouse models have not been fully understood. Here, we investigated the global and local neuroanatomy of the Mecp2 gene-deleted RTT model (Mecp2-KO) mouse brain using T2-weighted 3D magnetic resonance imaging with different morphometry to clarify the brain structural abnormalities that are involved in the pathophysiology of RTT. We found a significant reduction in global and almost all local volumes in the brain of Mecp2-KO mice. In addition, a detailed comparative analysis identified specific volume reductions in several brain regions in the Mecp2-deficient brain. Our analysis also revealed that the Mecp2-deficient brain shows changes in hemispheric asymmetry in several brain regions. These findings suggest that MeCP2 affects not only the whole-brain volume but also the region-specific brain structure. Our study provides a framework for neuroanatomical studies of a mouse model of RTT.

Congenital genetic disorders often present with neurological manifestations such as neurodevelopmental disorders, motor developmental retardation, epilepsy, and involuntary movement. Through qualitative morphometric evaluation of neuroimaging studies, remarkable structural abnormalities, such as lissencephaly, polymicrogyria, white matter lesions, and cortical tubers, have been identified in these disorders, while no structural abnormalities were identified in clinical settings in a large population. Recent advances in data analysis programs have led to significant progress in the quantitative analysis of anatomical structural magnetic resonance imaging (MRI) and diffusion-weighted MRI tractography, and these approaches have been used to investigate psychological and congenital genetic disorders. Evaluation of morphometric brain characteristics may contribute to the identification of neuroimaging biomarkers for early diagnosis and response evaluation in patients with congenital genetic diseases. This mini-review focuses on the methodologies and attempts employed to study Rett syndrome using quantitative structural brain MRI analyses, including voxel- and surface-based morphometry and diffusion-weighted MRI tractography. The mini-review aims to deepen our understanding of how neuroimaging studies are used to examine congenital genetic disorders.