[P27]: The effects of metabotropic glutamate antagonist on neural stem cells in fragile X syndrome

2006 ◽  
Vol 24 (8) ◽  
pp. 507-507
Author(s):  
M. Castrén ◽  
V. Kärkkäinen ◽  
K. Åkerman
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Metabotropic Glutamate ◽  
Glutamate Antagonist

scholarly journals Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

2022 ◽  
Author(s):  
Sahar Javadi ◽  
Yue Li ◽  
Jie Shen ◽  
Lucy Zhao ◽  
Yao Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Therapeutic Effects ◽  
Mature Adult ◽  
Mature Adults ◽  
Deficient Mice

Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

scholarly journals Altered differentiation of neural stem cells in fragile X syndrome

2005 ◽  
Vol 102 (49) ◽  
pp. 17834-17839 ◽  
Author(s):  
M. Castren ◽  
T. Tervonen ◽  
V. Karkkainen ◽  
S. Heinonen ◽  
E. Castren ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Fragile X Syndrome ◽  
Fragile X

scholarly journals Impaired inhibitory control of cortical synchronization in fragile X syndrome

2011 ◽  
Vol 106 (5) ◽  
pp. 2264-2272 ◽  
Author(s):  
Scott M. Paluszkiewicz ◽  
Jose Luis Olmos-Serrano ◽  
Joshua G. Corbin ◽  
Molly M. Huntsman
Keyword(s):  
Fragile X Syndrome ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Synaptic Inhibition ◽  
Cortical Interneuron ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Functional Defect

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

scholarly journals Developmental Study of Fragile X Syndrome Using Human Embryonic Stem Cells Derived from Preimplantation Genetically Diagnosed Embryos

2007 ◽  
Vol 1 (5) ◽  
pp. 568-577 ◽  
Author(s):  
Rachel Eiges ◽  
Achia Urbach ◽  
Mira Malcov ◽  
Tsvia Frumkin ◽  
Tamar Schwartz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Fragile X Syndrome ◽  
Human Embryonic Stem Cells ◽  
Fragile X ◽  
Embryonic Stem ◽  
Developmental Study
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