Abstract
Rett syndrome (RTT) is a severe neurodevelopmental disorder associated with mutations in either MECP2, CDKL5 or FOXG1. The precise molecular mechanisms that lead to the pathogenesis of RTT have yet to be elucidated. We recently reported that expression of GluD1 (orphan glutamate receptor δ-1 subunit) is increased in iPSC-derived neurons obtained from patients with mutations in either MECP2 or CDKL5. GluD1 controls synaptic differentiation and shifts the balance between excitatory and inhibitory synapses toward the latter. Thus, an increase in GluD1 might be a critical factor in the etiology of RTT by affecting the excitatory/inhibitory balance in the developing brain. To test this hypothesis, we generated iPSC-derived neurons from FOXG1+/− patients. We analyzed mRNA and protein levels of GluD1 together with key markers of excitatory and inhibitory synapses in these iPSC-derived neurons and in Foxg1+/− mouse fetal (E11.5) and adult (P70) brains. We found strong correlation between iPSC-derived neurons and fetal mouse brains, where GluD1 and inhibitory synaptic markers (GAD67 and GABA AR-α1) were increased, whereas the levels of a number of excitatory synaptic markers (VGLUT1, GluA1, GluN1 and PSD-95) were decreased. In adult mice, GluD1 was decreased along with all GABAergic and glutamatergic markers. Our findings further the understanding of the etiology of RTT by introducing a new pathological event occurring in the brain of FOXG1+/− patients during embryonic development and its time-dependent shift toward a general decrease in brain synapses.
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Acknowledgements
The “Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases”, member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, and of the EuroBioBank network and the “Associazione Italiana Rett O.N.L.U.S.”, provided us with specimens. We acknowledge the following grant support: NIMH MH089176 and MH087879 from the National Institute of Health (NIH) USA to FMV. We thank Livia Tomasini and Jessica Mariani (Child Study Center, Yale University, USA) for their help. This work was supported by Telethon (GGP09117 to AR), Italian Health Ministry (RF-2010-2317597 to AR) and the National Institutes of Health (R01NS078792 to JWH).
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Patriarchi, T., Amabile, S., Frullanti, E. et al. Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1+/− patients and in foxg1+/− mice. Eur J Hum Genet 24, 871–880 (2016). https://doi.org/10.1038/ejhg.2015.216
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DOI: https://doi.org/10.1038/ejhg.2015.216
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