Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons
Shreya Das Sharma,
Bharath Kumar Reddy,
Rakhi Pal,
Tuula E. Ritakari,
James D. Cooper,
Bhuvaneish T. Selvaraj,
Peter C. Kind,
Siddharthan Chandran,
David J.A. Wyllie,
Sumantra Chattarji
Affiliations
Shreya Das Sharma
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India; University of Trans-Disciplinary Health Science and Technology, Bangalore 560064, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, Chancellor’s Building, Edinburgh EH16 4SB, UK
Bharath Kumar Reddy
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India
Rakhi Pal
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India
Tuula E. Ritakari
Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, Chancellor’s Building, Edinburgh EH16 4SB, UK
James D. Cooper
Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, Chancellor’s Building, Edinburgh EH16 4SB, UK
Bhuvaneish T. Selvaraj
Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, Chancellor’s Building, Edinburgh EH16 4SB, UK
Peter C. Kind
Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK
Siddharthan Chandran
Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, Chancellor’s Building, Edinburgh EH16 4SB, UK; Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK
David J.A. Wyllie
Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Corresponding author
Sumantra Chattarji
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India; Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India; Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Corresponding author
Summary: Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100β, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons.
