Modeling the interplay between neurons and astrocytes in autism using human induced pluripotent stem cells
Biological Psychiatry, Available online 3 October 2017
Fabiele Baldino Russo, Beatriz Camille Freitas, Graciela Conceição Pignatari, Isabella Rodrigues Fernandes, Jonathan Sebat, Alysson Renato Muotri, Patricia Cristina Baleeiro Beltrão-Braga
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil Department of Surgery, School of Veterinary Medicine, University of São Paulo, São Paulo, SP,
Brazil Department of Pediatrics/Rady Children’s Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA Department of Psychiatry, Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA Department of Obstetrics, School of Arts, Sciences and Humanities, University of São Paulo, São Paulo, SP, Brazil Received 12 September 2016, Revised 14 August 2017, Accepted 17 September 2017,
Abstract
Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with unclear etiology and imprecise genetic causes. The main goal of this work was to investigate neuronal connectivity and the interplay between neurons and astrocytes from non-syndromic ASD individuals using induced Pluripotent Stem Cells (iPSCs).
Methods Our iPSCs were derived from a clinically well-characterized cohort of three non-syndromic ASD individuals, sharing common behaviors, and three controls, two clones each. We generated mixed neural cultures analyzing synaptogenesis and neuronal activity using a multi-electrode array (MEA) platform. Furthermore, using an enriched astrocytes population we investigated their role in neuronal maintenance.
Results Our results revealed that ASD-derived neurons had a significant decrease in synaptic gene expression and protein levels, glutamate neurotransmitter release and, consequently, reduced spontaneous firing rate. Based on co-culture experiments, we observed that ASD-derived astrocytes interfered with proper neuronal development. In contrast, control-derived astrocytes rescued the morphological neuronal phenotype and synaptogenesis defects from ASD neuronal co-cultures. Furthermore, after identifying IL-6 secretion from astrocytes in our ASD individuals as a possible culprit for neural defects, we were able to increase synaptogenesis by blocking IL-6 levels.
Conclusions Our findings reveal astrocytes contribution to neuronal phenotype and confirm previous studies linking IL-6 and autism, suggesting potential novel therapeutic pathways for a subtype of ASD individuals. This is the first report demonstrating that glial dysfunctions could contribute to non-syndromic autism pathophysiology using iPSCs modeling disease technology.
