TY - JOUR
T1 - Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons
AU - Das Sharma, Shreya
AU - Reddy, Bharath Kumar
AU - Pal, Rakhi
AU - Ritakari, Tuula E
AU - Cooper, James D
AU - Thangaraj Selvaraj, Bhuvaneish
AU - Kind, Peter C
AU - Chandran, Siddharthan
AU - Wyllie, David J. A.
AU - Chattarji, Sumantra
N1 - Funding Information:
Funding: Department of Biotechnology, Government of India BT/MB-CNDS/2013 (S. Chattarji); Simons Foundation Autism Research Initiative 529085 (P.C.K.); and The Patrick Wild Centre and Medical Research Council UK MR/P006213/1 (P.C.K., S. Chandran, D.J.A.W., S. Chattarji).
Funding Information:
We thank Loren Ornelas, Dhruv Sareen, and Clive Svendsen for providing us with the reprogrammed cell lines CS25iCTR-18n6 (CON), CS848iFXS-n5 (FXS1), and CS072iFXS-n4 (FXS2). We thank Nikhita Annaiyappa and Aaveri Sengupta, and the Central Imaging and Flow Facility at NCBS, for their assistance. We gratefully acknowledge all lab members for providing constructive comments. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Graphical Abstract and Figure S1 were created using Biorender.com. For the purpose of Open Access, the authors have applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission. Funding: Department of Biotechnology, Government of India BT/MB-CNDS/2013 (S. Chattarji); Simons Foundation Autism Research Initiative 529085 (P.C.K.); and The Patrick Wild Centre and Medical Research Council UK MR/P006213/1 (P.C.K. S. Chandran, D.J.A.W. S. Chattarji). S.D.S. B.K.R. R.P. T.E.R. J.D.C. B.T.S. P.C.K. S. Chandran, D.J.A.W. and S. Chattarji were responsible for the conception and design of the experiments. S.D.S. performed all the electrophysiological recordings. B.K.R. and R.P. carried out human stem cell (hPSC) culture, including propagation and characterization of the cell lines. B.K.R. carried out all the astrocyte culture, including propagation and characterization of the hPSC-derived astrocytes. S.D.S. B.K.R. R.P. T.E.R. J.D.C. and B.T.S. were responsible for the collection and assembly of data. S.D.S. B.K.R. R.P. T.E.R. J.D.C. B.T.S. P.C.K. S. Chandran, D.J.A.W. and S. Chattarji were responsible for the analysis and interpretation of data. S.D.S. B.K.R. R.P. B.T.S. P.C.K. S. Chandran, D.J.A.W. and S. Chattarji wrote the manuscript, and all authors had the opportunity to contribute to its editing. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The authors read and approved the final manuscript. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/4/25
Y1 - 2023/4/25
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2023.112344
DO - 10.1016/j.celrep.2023.112344
M3 - Article
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 4
M1 - 112344
ER -