The Study Of UiPSC-derived Neuron Model Of An Autistic Savant With Exceptional Memory

Autism spectrum disorders(ASDs)are a heterogeneous group of complex neurodevelopmental disorders(NDDs)without unique and definite underlying pathogenesis.According to the recent surveys,the prevalence of ASD was approximately 1% in the world,higher in males than females.Savant syndrome is common in ASDs,and they are autistic savants.Most of autistic savants for researches are rare and special cases,while few cell models are available for studying the physiological pathologies of autistic savants.Here we reprogramed exfoliated renal epithelial cells isolated from the urine of the autistic savant into urinary induced pluripotent stem cell(Ui PSC)models,by using the human induced pluripotent stem cell(hi PSC)approach.The 13-yearold male autistic savant with exceptional memory,photographic memory,was also diagnosed having a severe speech-language deficit.On the early stage of differentiation and maturation(day 42),autistic savant Ui PSC-derived neurons exhibited upregulated expression levels of ASD genes/learning difficulty-related genes,namely PAX6,TBR1 and FOXP2,downregulated glutamic acid decarboxylase 65(GAD65),decreased phosphorylation of subunit NR2 B of Nmethyl-D-aspartic acid(NMDA)receptor,accompanied by hypertrophic neural somas,enlarged spines,reduced spine density,and an increased frequency of spontaneous excitatory postsynaptic currents(s EPSCs).It has been very hard to find other autistic savant with “the rain man”-like photographic memory and severe speech-language deficit.The clinical case is extremely rare in this study.Notably,in most previous reports on ASD and intellectual disability,PAX6,TBR1 and FOXP2 were either deficiently expressed or had lost functions.TBR1 mutations have been implicated in impairments in social interaction,vocalization,memory and cognition.PAX6 and FOXP2 have also been observed to be involved in the regulation of higher cognitive functions including speech and language.In the present study,all of them were upregulated in the Ui PSC-derived neurons of the autistic savant.PAX6,TBR1,and FOXP2 upregulation provides a new idea for the exceptional memory along with the speech-language deficit of the idiopathic autistic savant.In a previous mouse model,Tbr1 promotes synapse numbers through Wnt7 b.The downstream TBR1 target genes CDH10,GPC6,LMO7,and CNTN2,which encode membrane proteins that regulate cell adhesion and axonal outgrowth,were upregulated in the Ui PSC-derived neurons of the autistic savant.The upregulation of these genes may explain the hypertrophic neural somas with enlarged spines and reduced spine density in the Ui PSC-derived neurons of the autistic savant.To further explain the changes in soma size and dendritic spine density and size and find key pathways,studies on autistic savant regarding TBR1 knockdown in Ui PSC-derived neurons must be conduced in the future.Moreover,the Ui PSC models of the autistic savant lay foundations for further research on the roles of important risk genes in the physiological and pathological mechanisms of autistic savants by using the clustered regularly interspaced short palindromic repeats/Cas(CRISPR/Cas)system in the future.