GABAA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability. FXS is caused by functional loss of the Fragile X Protein (FXP), also known as Fragile X Mental Retardation Protein (FMRP). In humans and animal models, loss of FXP leads to sensory hypersensitivity, increased susceptibility to seizures and cortical hyperactivity. Several components of the GABAergic system, the major inhibitory system in the brain, are dysregulated in FXS, and thus modulation of GABAergic transmission was suggested and tested as a treatment strategy. However, so far, clinical trials using broad spectrum GABAA or GABAB receptor-specific agonists have not yielded broad improvement of FXS phenotypes in humans. Here, we tested a more selective strategy in Fmr1 knockout (KO) mice using the experimental drug BAER-101, which is a selective GABAA α2/α3 agonist. Our results suggest that BAER-101 reduces hyperexcitability of cortical circuits, partially corrects increased frequency-specific baseline cortical EEG power, reduces susceptibility to audiogenic seizures and improves novel object memory. Other Fmr1 KO-specific phenotypes were not improved by the drug, such as increased hippocampal dendritic spine density, open field activity and marble burying. Overall, this work shows that BAER-101 improves select phenotypes in Fmr1 KO mice and encourages further studies into the efficacy of GABAA-receptor subunit-selective agonists for the treatment of FXS.

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Fragile X syndrome patient-derived neurons developing in the mouse brain show FMR1 -dependent phenotypes

10.1101/2021.09.27.461739 ◽

2021 ◽

Author(s):

Marine A Krzisch ◽

Hao A Wu ◽

Bingbing Yuan ◽

Troy W. Whitfield ◽

X. Shawn Liu ◽

...

Keyword(s):

Fragile X Syndrome ◽

Neuronal Development ◽

Fragile X ◽

In Vitro Models ◽

Synaptic Activity ◽

Human Neurons ◽

Induced Pluripotent ◽

And Function ◽

The Brain

Abnormal neuronal development in Fragile X syndrome (FXS) is poorly understood. Data on FXS patients remain scarce and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. Here, we co-injected neural precursor cells (NPCs) from FXS patient-derived and corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Single-cell RNA sequencing of transplanted cells revealed upregulated excitatory synaptic transmission and neuronal differentiation pathways in FXS neurons. Immunofluorescence analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, increased percentages of Arc- and Egr1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons pointed to an increase in synaptic activity and synaptic strength as compared to control. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3D context, and could be used to test new therapeutic compounds correcting neuronal development defects in FXS.

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A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Genome Research ◽

10.1101/gr.116764.110 ◽

2011 ◽

Vol 21 (12) ◽

pp. 2190-2202 ◽

Cited By ~ 67

Author(s):

L. Davidovic ◽

V. Navratil ◽

C. M. Bonaccorso ◽

M. V. Catania ◽

B. Bardoni ◽

...

Keyword(s):

Systems Biology ◽

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

The Brain

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Seizing control of fragile X syndrome

Science Translational Medicine ◽

10.1126/scitranslmed.aba2902 ◽

2020 ◽

Vol 12 (524) ◽

pp. eaba2902

Author(s):

Emily K. Osterweil

Keyword(s):

Mouse Model ◽

Inferior Colliculus ◽

Fragile X Syndrome ◽

Fragile X ◽

Audiogenic Seizures ◽

Glutamatergic Neurons

Loss of Fmr1 in glutamatergic neurons of the inferior colliculus is responsible for audiogenic seizures in the fragile X syndrome mouse model.

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A Drosophila model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells

The Journal of Cell Biology ◽

10.1083/jcb.201607093 ◽

2017 ◽

Vol 216 (3) ◽

pp. 595-605 ◽

Cited By ~ 19

Author(s):

Reed M. O’Connor ◽

Elizabeth F. Stone ◽

Charlotte R. Wayne ◽

Emily V. Marcinkevicius ◽

Matt Ulgherait ◽

...

Keyword(s):

Fragile X Syndrome ◽

Immune Cells ◽

Rna Binding ◽

Fragile X ◽

The Body ◽

Innate Immune ◽

Drosophila Model ◽

A Cell ◽

Increased Sensitivity ◽

The Brain

Fragile X syndrome, the most common known monogenic cause of autism, results from the loss of FMR1, a conserved, ubiquitously expressed RNA-binding protein. Recent evidence suggests that Fragile X syndrome and other types of autism are associated with immune system defects. We found that Drosophila melanogaster Fmr1 mutants exhibit increased sensitivity to bacterial infection and decreased phagocytosis of bacteria by systemic immune cells. Using tissue-specific RNAi-mediated knockdown, we showed that Fmr1 plays a cell-autonomous role in the phagocytosis of bacteria. Fmr1 mutants also exhibit delays in two processes that require phagocytosis by glial cells, the immune cells in the brain: neuronal clearance after injury in adults and the development of the mushroom body, a brain structure required for learning and memory. Delayed neuronal clearance is associated with reduced recruitment of activated glia to the site of injury. These results suggest a previously unrecognized role for Fmr1 in regulating the activation of phagocytic immune cells both in the body and the brain.

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Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome

Science Translational Medicine ◽

10.1126/scitranslmed.aam8572 ◽

2020 ◽

Vol 12 (544) ◽

pp. eaam8572 ◽

Cited By ~ 4

Author(s):

Patrick K. McCamphill ◽

Laura J. Stoppel ◽

Rebecca K. Senter ◽

Michael C. Lewis ◽

Arnold J. Heynen ◽

...

Keyword(s):

Protein Synthesis ◽

Mouse Model ◽

Fragile X Syndrome ◽

Animal Studies ◽

Metabotropic Glutamate Receptor ◽

Glycogen Synthase ◽

Fragile X ◽

Selective Inhibition ◽

Audiogenic Seizures ◽

Glycogen Synthase Kinase

Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1−/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and β paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased β-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1−/y mice. Although inhibiting either paralog prevented induction of NMDA receptor–dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis–dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1−/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.

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Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

10.1101/2020.04.19.048819 ◽

2020 ◽

Author(s):

Marta Prieto ◽

Alessandra Folci ◽

Gwénola Poupon ◽

Sara Schiavi ◽

Valeria Buzzelli ◽

...

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Long Term Potentiation ◽

Surface Expression ◽

Missense Mutations ◽

Spine Density ◽

Cgg Repeat ◽

Electrophysiological Recordings ◽

Receptor Surface Expression

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1R138Q mice. These findings reveal that the R138Q mutation impacts the synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.

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Pioglitazone improves deficits of Fmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling

10.1101/2020.09.22.301762 ◽

2020 ◽

Author(s):

Andréa Geoffroy ◽

Karima Habbas ◽

Boglarka Zambo ◽

Laetitia Schramm ◽

Arnaud Duchon ◽

...

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Rna Binding ◽

Fragile X ◽

Loss Of Function ◽

Behavioral Alterations ◽

Specific Proteins ◽

The Brain

AbstractFragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling in Fmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of the Fmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS.

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