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 Thangaraj Selvaraj, Peter C Kind, Siddharthan Chandran, David J. A. Wyllie, Sumantra Chattarji

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Article number112344
JournalCell Reports
Issue number4
Early online date4 Apr 2023
Publication statusPublished - 25 Apr 2023


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