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Achuta, Venkat Swaroop; Grym, Heli; Putkonen, Noora; Louhivuori, Verna; Kärkkäinen, Virve; Koistinaho, Jari; Roybon, Laurent; Castrén, Maija

doi:10.1002/dneu.22494

Cited by 1 publication

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“…This phenomenon can be ascribed either to a functional upregulation of glutamatergic receptors, or to an increased depolarizing response, as reported for mouse neuronal progenitors lacking FMRP [47,48]. Moreover, although at day 70 the number of glutamatergic synapses was similar in FMRP-WT and FMRP-KO cortical cultures, as revealed by the pre (VGLUT1) and post-synaptic (PSD95) staining, we cannot exclude a different contribution of ionotropic and metabotropic glutamate receptors between the two genotypes in mediating the neuronal depolarization that might contribute to glutamate-induced calcium transients, as in murine neuronal progenitors [49].…”

Section: Discussionmentioning

confidence: 56%

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Brighi

Salaris

Soloperto

et al. 2020

Preprint

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Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

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Section: Discussionmentioning

confidence: 56%