1198620_Allen,M_2022.pdf (9.4 MB)
Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling
journal contributionposted on 2022-06-17, 04:49 authored by M Allen, BS Huang, MJ Notaras, A Lodhi, E Barrio-Alonso, PJ Lituma, P Wolujewicz, J Witztum, F Longo, M Chen, David GreeningDavid Greening, E Klann, ME Ross, C Liston, D Colak
The cellular mechanisms of autism spectrum disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes regulate several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity. Astrocyte abnormalities have also been identified in the postmortem brain tissue of ASD individuals. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we combined stem cell culturing with transplantation techniques to determine disease-specific properties inherent to ASD astrocytes. We demonstrate that ASD astrocytes induce repetitive behavior as well as impair memory and long-term potentiation when transplanted into the healthy mouse brain. These in vivo phenotypes were accompanied by reduced neuronal network activity and spine density caused by ASD astrocytes in hippocampal neurons in vitro. Transplanted ASD astrocytes also exhibit exaggerated Ca2+ fluctuations in chimeric brains. Genetic modulation of evoked Ca2+ responses in ASD astrocytes modulates behavior and neuronal activity deficits. Thus, this study determines that astrocytes derived from ASD iPSCs are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.
We thank the WCM Proteomics Core facility for providing experimental consultation and results. Especially, Dr. Guoan Zhang, the director, and two associate members, Mengmeng Zhu and Taojunfeng Su. We also thank the WCM Genomics Resources Core Facility for consultation and WES sequencing. Additionally, we thank Dr. Zhengming Chen, Ph.D., M.P.H., M.S., a senior research biostatistician in the Division of Biostatistics and Epidemiology at Weill Cornell Medicine, for statistical power analysis. We would like to thank Dr. Lavo Ramos-Espiritu and the High Throughput and Spectroscopy Resource Center at Rockefeller University for training on plate reader for Ca2 imaging experiments and valuable comments. This work was supported by a NIH grant 1R01MH120156-01 to DC.
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Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyNeurosciencesPsychiatryNeurosciences & NeurologyGLIAL PROGENITOR CELLSCOPY-NUMBER VARIATIONSYNAPTIC PLASTICITYCEREBRAL ORGANOIDSEXECUTIVE FUNCTIONAUTISTIC TRAITSMOUSE MODELSBRAINPHENOTYPESGLUTAMATEAnimalsAstrocytesAutism Spectrum DisorderHippocampusMiceNeuronal PlasticityNeuronsSynapsesNeurosciences not elsewhere classified