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We thank Julie Shabto, Qanetha Ahmed, Yelizaveta Gribkova, and Huber Rodriguez-Tejada for their contribution to western Blotting and imaging experiments. We thank Luis Aparicio de Santiago for his contribution to the scRNAseq analysis. We thank Joseph Sall from NYU Langone’s Microscopy Laboratory (supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center) for technical assistance with the light-sheet microscopy image acquisition. Alexander Sosunov, Andrew Dwork and Gorazd Rosoklija for their advice on histology experiments. Maura Boldrini for her advice on the BrdU labeling experiments. Yuanjia Wang and Chen Chen for their advice on the statistical analyses using the linear mixed model. T1 - Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder We thank Joseph Sall from NYU Langone 2021, The Author(s).", Note = "Funding Information: The authors would like to thank Dr. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.", The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. Moreover, the DEgenes are enriched for ASD-associated genes. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation.
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Patients with this mutation present with clinical characteristics of brain overgrowth. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.Ībstract = "We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Here we review our current knowledge, on antibody mediated autoimmunity in psychotic disorders, the different diagnostic methods and their limitations, as well as on varying therapeutic approaches targeting the immune system.We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. The overlap of symptoms of autoimmune encephalitis with psychotic disorders raised the question as to whether autoantibodies against a number of receptors, ion channel and associated proteins could ultimately be responsible for some forms of psychosis. These autoantibodies disrupt neurotransmission within the brain, resulting in a wide range of psychiatric and neurologic manifestations, including psychosis. The development of disease-modifing therapies has been hampered by the mostly unknown etiologies and pathophysiologies.Īutoantibodies against several neuronal antigens are responsible for autoimmune encephalitis. Psychotic disorders are debilitating mental illnesses associated with abnormalities in various neurotransmitter systems.