AUTHOR=Takahashi Emi , Allan Nina , Peres Rafael , Ortug Alpen , van der Kouwe Andre J. W. , Valli Briana , Ethier Elizabeth , Levman Jacob , Baumer Nicole , Tsujimura Keita , Vargas-Maya Nauru Idalia , McCracken Trevor A. , Lee Rosa , Maunakea Alika K. 

TITLE=Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 16 - 2022

YEAR=2023

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.1023665

DOI=10.3389/fnins.2022.1023665

ISSN=1662-453X

ABSTRACT=Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication and repetitive, restrictive behaviors. Despite the increasing global prevalence of ASD, recently estimated to affect 100 in 10,000 (or 1 in 100) children, its underlying etiology remains poorly understood. Given recent studies linking defects in cell migration and proliferation in the subventricular zone (SVZ) to ASD-like symptoms, we explored molecular, cellular, and structural changes in the SVZ and cortical regions of brain specimens of ASD diagnosed and unaffected, typically developing individuals in a case study. In applying MRI to these cases, we observed decreased tractography pathways from the dorsal SVZ and increased pathways from the posterior ventral SVZ to the insular cortex, together with variable cortical thickness within the insular cortex in ASD relative to control samples. Long-range tractography pathways from/ and to the insula were also reduced in the ASD. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD relative to the control sample. 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. Altogether, these preliminary findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the patterns of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in the phenotypes that characterize ASD.