Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

Wang, Lu; Wang, Yan; Zhou, Shimeng; Yang, Liu-kun; Shi, Qingqing; Li, Yujiao; Zhang, Kun; Yang, Le; Zhao, Ming; Yang, Qi

doi:10.3390/genes7080045

Cited by 22 publications

(14 citation statements)

References 56 publications

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“…Thus, these findings from different studies in the FXS animal models confirmed that GABA receptors are suitable targets for target treatment in FXS [18,39,95,96,97,98,99,100,101,102,103]. Indeed, two phase 3 placebo-controlled trials were conducted (with subjects aged 12–50 and in subjects aged 5–11) to determine the safety and efficacy of arbaclofen for improving social behavior in FXS patients.…”

Section: γ-Aminobutyric Acid (Gaba) Receptorsmentioning

confidence: 69%

Molecular Biomarkers in Fragile X Syndrome

Zafarullah

Tassone

2019

Brain Sciences

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Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

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Section: γ-Aminobutyric Acid (Gaba) Receptorsmentioning

confidence: 69%

Molecular Biomarkers in Fragile X Syndrome

Zafarullah

Tassone

2019

Brain Sciences

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“…Indeed, a delay in the switch of the chloride reversal potential has been reported in cortical neurons of Fmr1 KO mice, causing the change in GABA transmission polarity, which in turn might affect neuronal development in the cortex of Fmr1 KO mice [59]. In summary, we can speculate that, in FMRP-KO coltures, beside the unbalance of glutamatergic and GABAergic systems, the upregulation of astrocytes may contribute to the enhancement of network activity [60].…”

Section: Discussionmentioning

confidence: 99%

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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“…The open-field test was conducted as described previously [ 22 ]. The test was carried out in a square arena (30 cm × 30 cm × 30 cm) made of clear plexiglass walls and flooring, which was placed inside an isolation chamber with dim illumination and a fan.…”

Section: Methodsmentioning

confidence: 99%

Tea polyphenols protect learning and memory in sleep-deprived mice by promoting AMPA receptor internalization

Xie

Wei

et al. 2020

NeuroReport

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Chronic sleep loss caused lots of health problems, also including cognition impairment. Tea is one of the most popular drinks when people stay up late. Nevertheless, the effects of tea on sleep deprivation-induced cognition impairment are still unclear. In the present study, we found 24-h sleep deprivation (S-DEP) increased membrane α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate (AMPA) receptor level through a tumor necrosis factor α (TNFα)-dependent pathway in hippocampi. Blocking elevated TNFα level can protect S-DEP mice from impaired learning ability according to behavioral test. Tea polyphenols, major active compounds in green tea, suppressed TNFα production through downregulating TNFα converting enzyme (TACE) level. Meanwhile, tea polyphenols treatment could ameliorate recognition impairment and anxiety-like behaviors in S-DEP mice. The aforementioned results demonstrate cognition protective effects of tea polyphenols in S-DEP mice model, which provide a theoretical basis for the treatments of S-DEP-induced cognition impairment by targeting the TACE/TNFα/AMPA pathway.

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Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

Cited by 22 publications

References 56 publications

Molecular Biomarkers in Fragile X Syndrome

Molecular Biomarkers in Fragile X Syndrome

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

Tea polyphenols protect learning and memory in sleep-deprived mice by promoting AMPA receptor internalization

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