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-1) 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 871-880 |
| Number of pages | 10 |
| Journal | European Journal of Human Genetics |
| Volume | 24 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2016 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1 patients and in foxg1 mice. / Patriarchi, Tommaso; Amabile, Sonia; Frullanti, Elisa; Landucci, Elisa; Lo Rizzo, Caterina; Ariani, Francesca; Costa, Mario; Olimpico, Francesco; Hell, Johannes W; Vaccarino, Flora M.; Renieri, Alessandra; Meloni, Ilaria.
In: European Journal of Human Genetics, Vol. 24, No. 6, 01.06.2016, p. 871-880.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1 patients and in foxg1 mice
AU - Patriarchi, Tommaso
AU - Amabile, Sonia
AU - Frullanti, Elisa
AU - Landucci, Elisa
AU - Lo Rizzo, Caterina
AU - Ariani, Francesca
AU - Costa, Mario
AU - Olimpico, Francesco
AU - Hell, Johannes W
AU - Vaccarino, Flora M.
AU - Renieri, Alessandra
AU - Meloni, Ilaria
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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-1) 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.
AB - 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-1) 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.
UR - http://www.scopus.com/inward/record.url?scp=84943339642&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943339642&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2015.216
DO - 10.1038/ejhg.2015.216
M3 - Article
C2 - 26443267
AN - SCOPUS:84943339642
VL - 24
SP - 871
EP - 880
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 6
ER -