Astrocytes derived from ASD patients alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling

Colak, D.; Allen, M.; Huang, B. S.; Notaras, M. J.; Lodhi, A.; Barrio-Alonso, E.; Wolujewicz, P.; Witztum, J.; Longo, F.; Chen, M.; Greening, D.; Klann, E.; Ross, M. E.; Liston, C.

doi:10.1101/2021.10.11.463231

bioRxiv · 10.1101/2021.10.11.463231

Astrocytes derived from ASD patients alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling

Colak, D.·Allen, M.·Huang, B. S.·Notaras, M. J.·Lodhi, A.·Barrio-Alonso, E.·Wolujewicz, P.·Witztum, J.·Longo, F.·Chen, M.·Greening, D.·Klann, E.·Ross, M. E.·Liston, C.

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Abstract

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 play in 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 patients. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we strategically combined stem cell culturing with transplantation techniques to determine disease specific properties inherent to patient derived 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, we determine that ASD patient astrocytes are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.

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Colak, D., Allen, M., Huang, B. S., Notaras, M. J., Lodhi, A., Barrio-Alonso, E., Wolujewicz, P., Witztum, J., Longo, F., Chen, M., Greening, D., Klann, E., Ross, M. E., Liston, C.. 2021-10-12. Astrocytes derived from ASD patients alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling. https://doi.org/10.1101/2021.10.11.463231

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