RESUMO
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. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.
Assuntos
Transtorno do Espectro Autista/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Organoides/metabolismo , Prosencéfalo/metabolismo , Adolescente , Transtorno do Espectro Autista/genética , Diferenciação Celular , Proliferação de Células , Criança , Feminino , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Fenótipo , Análise de Sequência de RNARESUMO
Electroconvulsive therapy (ECT) is one of the most effective methods for managing treatment-resistant depression. Although the proposed mechanisms of action have thus far mainly been investigated at the cellular level, recent observations and developments in the field of molecular biology and genomics have provided novel insights in the actual molecular underpinnings of dynamic alterations in gene expression, particularly in response to environmental exposures, and experience-dependent plasticity, both of which are highly relevant to ECT. Here, we provided a brief background on epigenetics and we reviewed the current state of knowledge on epigenetic mediation of ECT-related therapeutic effects. We performed a systematic search on the effects of ECT on epigenetics and found only a limited number on animal studies relevant to our search. These studies, however, support the notion of a robust impact of ECT on epigenetic mechanisms and set the stage for human ECT studies on the epigenetic machinery.
